2-benzocoumarinyl-carbapenems

ABSTRACT

Carbapenems of the formula ##STR1## are useful intermediates to antibacterial agents.

Thienamycin was an early carbapenem antibacterial agent having a broadspectrum; it has the following formula: ##STR2## Later, N-formimidoylthienamycin was discovered; it has the formula: ##STR3##

The 2-benzocoumarinyl-carbapenems of the present invention are notcharacterized by a broad antibacterial spectrum such as that ofthienamycin or N-formimidoyl thienamycin. Rather, their spectrum ofactivity is largely limited to gram positive microorganisms, especiallymethicillin resistant Staphylococcus aureus (MRSA), methicillinresistant Staphylococcus epidermidis (MRSE), and methicillin resistantcoagulase negative Staphylococci (MRCNS). The antibacterial compounds ofthe present invention thus comprise an important contribution to therapyof these difficult to control pathogens. Moreover, there is anincreasing need for agents effective against such pathogens (MRSA/MRCNS)which are at the same time safe, i.e., free from undesirable toxic sideeffects. No β-lactam antibacterial has yet been found which meets theserequirements. And, the current agent of choice, vancomycin, aglycopeptide antibacterial, is experiencing an ever increasing amount ofresistance in the MRSA/MRCNS pathogens.

More recently, carbapenem antibacterial agents have been described whichhave a 2-substituent which is an aryl moiety optionally substituted by,e.g., aminomethyl and substituted aminomethyl. These agents aredescribed in U.S. Pat. Nos. 4,543,257 and 4,260,627 and have theformula: ##STR4##

However, there is no description or suggestion of a benzocoumarinyl2-substituent such as characterizes the compounds of the presentinvention, nor is there any suggestion of the suprisingly betteranti-MRSA/MRCNS activity of the compounds of the present invention.

U.S. Pat. No. 4,978,659 describes a particular class of compounds of theformula: ##STR5## but this limited teaching in no way suggests thetotally different compounds of the present invention, nor theirsurprisingly better anti-MRSA/MRCNS activity.

SUMMARY OF INVENTION

The present invention provides novel carbapenem compounds of theformula: ##STR6## wherein: R is H or CH₃ ;

R¹ and R² are independently H, CH₃ --, CH₃ CH₂ --, (CH₃)₂ CH--, HOCH₂--, CH₃ CH(OH)--, (CH₃)₂ C(OH)--, FCH₂ CH(OH)--, F₂ (CHCH(OH)--, F₃CCH(OH)--, CH₃ CH(F)--, CH₃ CF₂ --, or (CH₃)₂ C(F)--;

X^(h) is O or S;

R^(a) are independently selected from the group consisting of hydrogenand the radicals set out below, provided that one but not more than oneR^(a) is a Type I substituent, the remaining non-hydrogen substituentsbeing selected from Type II, and in total not more than four R^(a)radicals are other than hydrogen: ##STR7## where A is (CH₂)_(m)--Q--(CH₂)_(n), where m is 0 to 6 and n is 1 to 6 and Q is a covalentbond, O, S, SO, SO₂, NH, --SO₂ NH--, --NHSO₂ --, --CONH--, --NHCO--,--SO₂ N(C₁ -C₄ alkyl)--, --N(C₁ -C₄ alkyl)SO₂ --, --CON(C₁ -C₄ alkyl)--,--N(C₁ -C₄ alkyl)CO--, --CH═CH--, --CO--, --OC(O)--, --C(O)O-- or N(C₁-C₄ alkyl) and (CH₂)_(m) is attached to the benzocoumarinyl moiety;##STR8## is a 5- or 6-membered monocyclic heterocycle or an 8-, 9- or10-membered bicyclic heterocycle, the heterocycle containing a firstnitrogen in an aromatic 5- or 6-membered first ring, with attachment ofthe heterocycle to A by way of said first nitrogen and said firstnitrogen is quaternary by virtue of the attachment and ring bonds, withthe first ring containing 0 or 1 of either O or S, with the first ringcontaining 0 to 3 additional nitrogen atoms, with the first ringoptionally fused to a 3- or 4-membered moiety to form the optionalsecond ring, with the the moiety containing at least one carbon atom,with the moiety containing 0 or 1 of either O or S, with the moietycontaining 0 to 2 nitrogen atoms, and with the moiety being saturated orunsaturated and the second ring aromatic or non-aromatic;

R^(c) is R^(a) as defined under II below, hydrogen, or --NR^(y) R^(z)(where R^(y) and R^(z) are defined in II below), but independentlyselected from R^(a) and from each other if more than one R^(c) ispresent, and is attached to a carbon ring atom or a nitrogen heteroatomthe valency of which is not satisfied by the ring bonds;

p is 0 or 1; ##STR9## where ##STR10## is a 5- or 6-membered monocyclicheterocycle or an 8-, 9- or 10-membered bicyclic heterocycle, theheterocycle containing a first nitrogen in an aromatic 5- or 6-memberedfirst ring, with said first nitrogen quaternary by virtue of asubstituent R^(d) in addition to the ring bonds thereto, with said firstnitrogen neutral in the absence of a substituent R^(d), with attachmentof the heterocycle to A' by way of a carbon atom of a ring, with thefirst ring containing 0 or 1 of either O or S, with the first ringcontaining 0 to 2 additional nitrogen atoms, with the first ringoptionally fused to a 3- or 4-membered moiety to form the optionalsecond ring, with the moiety containing at least one carbon atom, withthe moiety containing 0 or 1 of either O or S, with the moietycontaining 0 to 2 nitrogen atoms, and with the moiety being saturated orunsaturated and the second ring aromatic or non-aromatic;

R^(c) is defined above;

R^(d) is hydrogen, NH₂, O⁻ or C₁ -C₄ alkyl (where the alkyl group isoptionally mono-substituted with R^(q) as defined under IIc below);

A' is (CH₂)_(m) --Q--(CH₂)_(n), where m is 0 to 6 and n is 0 to 6 and Qis given above;

c) --A_(p) --N⁺ R^(y) (R^(w))₀₋₁ (R^(z)) where

R^(y) and R^(z) are as defined under II below,

R^(y) and R^(z) may further be together a C₂ -C₄ alkylidene radical toform a ring (optionally mono-substituted with R^(q) as defined below)interrupted by N(O)R^(e) or N⁺ (R^(e))₂ (where R^(e) is hydrogen, C₁ -C₄alkyl, or C₁ -C₄ alkyl mono-substituted with R^(q) as defined below),

R^(w) is hydrogen, C₁₋₄ alkyl, O⁻, NH₂, or absent in which case thenitrogen is neutral,

R^(w), R^(y) and R^(z) may further together form a C₅ -C₁₀ tertiaryalkylidene radical which with N⁺ forms a bicyclic ring, where thetertiary alkylidene radical is optionally mono-substituted with R^(q) asdefined below and where the tertiary carbon of the tertiary alkylideneradical is optionally replaced with nitrogen, N⁺ R^(e) (where R^(e) isdefined above), or N⁺ --O⁻,

p is 0 or 1, and

A is as defined above; ##STR11## where ##STR12## is a 5- or 6-memberedmonocyclic heterocycle or an 8-, 9- or 10-membered bicyclic heterocycle,the heterocycle containing a first nitrogen in a first ring, with thefirst ring saturated or unsaturated and non-aromatic, with the firstnitrogen quaternary by virtue of one or two substituents R^(d) inaddition to the ring bonds thereto, with the first nitrogenalternatively neutral by virtue of zero or one substituents R^(d) inaddition to the ring bonds thereto with attachment of the heterocycle toA' by way of a carbon atom or non-quaternary nitrogen atom or a ring,with the first ring containing in addition to carbon and the firstnitrogen 0 to 1 of a member selected from the group consisting of thenon-quaternary nitrogen of attachment, O, S, S(O), S(O)₂ and NR^(e)where R^(e) is defined above, with the first ring optionally fused to a2-, 3- or 4-membered moiety to form the optional second ring, with themoiety optionally containing in addition to carbon the non-quaternarynitrogen of attachment, and with the moiety saturated or unsaturated andthe second ring non-aromatic;

R^(d) is defined above and where more than one R^(d) is present on anitrogen, at least one R^(d) is hydrogen or C₁ -C₄ alkyl;

A' is defined above; and

p is defined above;

R^(q) is defined below;

II.

a) a trifluoromethyl group: --CF₃ ;

b) a halogen atom: --Br, --Cl, --F, or --I;

c) C₁ -C₄ alkoxy radical: --OC₁₋₄ alkyl, wherein the alkyl is optionallymono-substituted by R^(q), where

R^(q) is a member selected from the group consisting of --OH, --OCH₃,--CN, --C(O)NH₂, --OC(O)NH₂, CHO, --OC(O)N(CH₃)₂, --SO₂ NH₂, --SO₂N(CH₃)₂, --SOCH₃, --SO₂ CH₃, --F, --CF₃, --COOM^(a) (where M^(a) ishydrogen, alkali metal, methyl or phenyl), tetrazolyl (where the pointof attachment is the carbon atom of the tetrazole ring and one of thenitrogen atoms is mono-substituted by M^(a) as defined above) and --SO₃M^(b) (where M^(b) is hydrogen or an alkali metal);

d) a hydroxy group: --OH;

e) a carbonyloxy radical: --O(C═O)R^(s), where

R^(s) is C₁₋₄ alkyl or phenyl, each of which is optionallymono-substituted by R^(q) as defined above or tri-substituted with --F;

f) a carbamoyloxy radical: --O(C═O)N(R^(y))R^(z) where

R^(y) and R^(z) are independently H, C₁₋₄ alkyl (optionallymono-substituted by R^(q) as defined above), together a 3- to 5-memberedalkylidene radical to form a ring (optionally substituted with R^(q) asdefined above) or together a 2- to 4-membered alkylidene radical,interrupted by --O--, --S--, --S(O)-- or --S(O)₂ -- to form a ring(where the ring is optionally mono-substituted with Rq as definedabove);

g) a sulfur radical: --S(O)_(n) --R^(s) where n=0-2, and R^(s) isdefined above;

h) a sulfamoyl group: --SO₂ N(R^(y))R^(z) where R^(y) and R^(z) are asdefined above;

i) azido: N₃

j) a formamido group: --N(R^(t))(C═O)H, where

R^(t) is H or C₁₋₄ alkyl, and the alkyl thereof is optionallymono-substituted by R^(q) as defined above;

k) a (C₁ -C₄ alkyl)carbonylamino radical: --N(R^(t))(C═O)C₁₋₄ alkyl,where R^(t) is as defined above, and the alkyl group is also optionallymono-substituted by R^(q) as defined above;

l) a (C₁ -C₄ alkoxy) carbonylamino radical: --N(R^(t))(C═O)OC₁₋₄ alkyl,where R^(t) is as defined above, and the alkyl group is also optionallymono-substituted by R^(q) as defined above;

m) a ureido group: --N(R^(t))C═O)N(R^(y))R^(z) where R^(t), R^(y) andR^(z) are as defined above;

n) a sulfonamido group: --N(R^(t))SO₂ R^(s), where R^(s) and R^(t) areas defined above;

o) a cyano group: --CN;

p) a formyl or acetalized formyl radical: --(C═O)H or --CH(OCH₃)₂ ;

q) (C₁ -C₄ alkyl)carbonyl radical wherein the carbonyl is acetalized:--C(OCH₃)₂ C₁₋₄ alkyl, where the alkyl is optionally mono-substituted byR^(q) as defined above;

r) carbonyl radical: --(C═O)R^(s), where R^(s) is as defined above;

s) a hydroximinomethyl radical in which the oxygen or carbon atom isoptionally substituted by a C₁ -C₄ alkyl group: --(C═NOR^(z))R^(y) whereR^(y) and R^(z) are as defined above, except they may not be joinedtogether to form a ring;

t) a (C₁ -C₄ alkoxy)carbonyl radical: --(C═O)OC₁₋₄ alkyl, where thealkyl is optionally mono-substituted by R^(q) as defined above;

u) a carbamoyl radical: --(C═O)N(R^(y))R^(z) where R^(y) and R^(z) areas defined above;

v) an N-hydroxycarbamoyl or N(C₁ -C₄ alkoxy)carbamoyl radical in whichthe nitrogen atom may be additionally substituted by a C₁ -C₄ alkylgroup: --(C═O)--N(OR^(y))R^(z) where R^(y) and R^(z) are as definedabove, except they may not be joined together to form a ring;

w) a thiocarbamoyl group: --(C═S)N(R^(y))(R^(z)) where R^(y) and R^(z)are as defined above;

x) carboxyl: --COOM^(b), where M^(b) is as defined above;

y) thiocyanate: --SCN;

z) trifluoromethylthio: --SCF₃ ;

aa) tetrazoyl, where the point of attachment is the carbon atom of thetetrazole ring and one of the nitrogen atoms is mono-substituted byhydrogen, an alkali metal or a C₁ -C₄ alkyl optionally substituted byR^(q) as defined above;

ab) an anionic function selected from the group consisting of: phosphono[P═O(OM^(b))₂ ]; alkylphosphono {P═O(OM^(b))--[O(C₁ -C₄ alkyl)]};alkylphosphinyl [P═O(OM^(b))--(C₁ -C₄ alkyl)]; phosphoramido[P═O(OM^(b))N(R^(y))R^(z) and P═O(OM^(b))NHR^(x) ]; sulfino (SO₂ M^(b));sulfo (SO₃ M^(b)); acylsulfonamides selected from the structuresCONM^(b) SO₂ R^(x), CONM^(b) SO₂ N(R^(y))R^(z), SO₂ NM^(b)CON(R^(y))R^(z) ; and SO₂ NM^(b) CN, where

R^(x) is phenyl or heteroaryl, where heteroaryl is a monocyclic aromatichydrocarbon group having 5 or 6 ring atoms, in which a carbon atom isthe point of attachment, in which one of the carbon atoms has beereplaced by a nitrogen atom, in which one additional carbon atom isoptionally replaced by a heteroatom selected from O or S, and in whichfrom 1 to 2 additional carbon atoms are optionally replaced by anitrogen heteroatom, and where the phenyl and heteroaryl are optionallymono-substituted by R^(q), as defined above; M^(b) is as defined above;and R^(y) and R^(z) are as defined above;

ac) C₅ -C₇ cycloalkyl group in which one of the carbon atoms in the ringis replaced by a heteroatom selected from O, S, NH or N(C₁ -C₄ alkyl)and in which one additional carbon atom may be replaced by NH or N(C₁-C₄ alkyl), and in which at least one carbon atom adjacent to eachnitrogen heteroatom has both of its attached hydrogen atoms replaced byone oxygen thus forming a carbonyl moiety and there are one or twocarbonyl moieties present in the ring;

ad) C₂ -C₄ alkenyl radical, optionally mono-substituted by one of thesubstituents a) to ac) above and phenyl which is optionally substitutedby R^(q) as defined above;

ae) C₂ -C₄ alkynyl radical, optionally mono-substituted by one of thesubstituents a) to ac) above;

af) C₁ -C₄ alkyl radical;

ag) C₁ -C₄ alkyl mono-substituted by one of the substituents a)-ac)above;

ah) a 2-oxazolidinonyl moiety in which the point of attachment is thenitrogen atom of the oxazolidinone ring, the ring oxygen atom isoptionally replaced by a heteroatom selected from --S-- and NR^(t)(where R^(t) is as defined above) and one of the saturated carbon atomsof the oxazolidinone ring is optionally mono-substituted by one of thesubstituents a) to ag) above; and

M is selected from:

i) hydrogen;

ii) a pharmaceutically acceptable esterifying group or removablecarboxyl protecting group;

iii) an alkali metal or other pharmaceutically acceptable cation; or

iv) a negative charge which is balanced by a positively charged group.

The present invention also provides novel carbapenem intermediates ofthe formula: ##STR13## wherein: R is H or CH₃ ;

X^(h) is O or S;

R^(a) is defined above, with the proviso that R^(q) additionallyincludes OP' where P' is defined below, that M^(a) and M^(b) of R^(q)both include M and that the Type d) hydroxy substituent additionally maybe protected hydroxy, OP';

P' is a removable protecting group for hydroxy; and

M is a removable protecting group for carboxy;

and the Type I, R^(a) substituent is balanced with the anionic form of Zwhere

Z is methanesulfonyloxy, trifluoromethanesulfonyloxy, fluorosulfonyloxy,p-toluenesulfonyloxy, 2,4,6-triisopropylbenzenesulfonyloxy,p-bromobenzenesulfonyloxy, p-nitrobenzenesulfonyloxy, bromo and iodo.Preferred intermediates have the formula: ##STR14## wherein R is --H or--CH₃ ;

R^(a) is selected from the group consisting of H, OP', Cl, Br, I, SCH₃,CN, CHO, SOCH₃, SO₂ CH₃, CO₂ M, CH₂ OP' or CONH₂ ;

P' is a removable protecting group for hydroxy;

M is a removable protecting group for carboxy; and

Z is selected from the group consisting of alkylsulfonyloxy, substitutedalkylsulfonyloxy, arylsulfonyloxy, substituted arylsulfonyloxy,fluorosulfonyloxy, and halogen; and with the proviso that the --CH₂ --Zmoiety is in the 3-or 4-position of the benzocoumarin as numbered above.

DETAILED DESCRIPTION OF THE INVENTION

The manufacture of compounds of Formula I may be carried out in athree-stage synthesis scheme followed by a final step which allows forthe removal of any protecting groups. The objective of the firstsynthetic stage is to produce a base benzocoumarin compound which may beconverted to the two-position substituent of the carbapenem of FormulaI. The objective of the second synthetic stage is to attach the basebenzocoumarin to the carbapenem. Finally, the objective of the thirdsynthetic stage is to substitute the benzocoumarin with the desiredR^(a). This third synthetic stage may be performed after the firstsynthetic stage or during or after the second synthetic stage accordingto the nature of the various R^(a).

Flow Sheets A1 and A2 demonstrate a suggested first stage synthesis.Flow Sheets B and C demonstrate two alternative second stage syntheses.The third synthesis varies according to the selected R^(a).

The suggested first synthesis herein, Flow Sheets A1 and A2, can begenerally described as a directed ortho metalation reaction to preparestarting materials required for a Suzuki cross-coupling reaction andfinally ring closure to produce the desired benzocoumarin platform. Thissuggested first synthesis is utilized to produce similar benzocoumarincompounds by Snieckus, V., Chem. Rev. 1990, 90, 879-933; Sharp, M. J.and Sniekus V., Tetrahedron Lett., 1985, 26, 5977-6000. A similarproduction of biaryls and phenanthridones may be analogously applied tobenzocoumarins and is described by Fu, J. M. and Snieckus, V.,Tetrahedron Lett. 1990, 31, 1665; Siddiqui, M. A., et al., TetrahedronLett., 1988, Vol. 29, 5463-5466; Mills, R. J., et al., J. Org. Chem.,1989, 54, 4372-4385; and Suzuki, A., et al., Syn. Comm., 1981, 11,513-519.

Referring to Flow Sheet A1 compound A1-1 is substituted with a directedmetalation group (DMG) by methods according to Snieckus, et al., above.The function of the directed metalation group (DMG) is to orchestrateadornment of the aromatic ring. It is highly desirable of the DMG thatit also provide a precursor substituent for the necessary carboxyfunction or phenolic function forming the lactone linkage of the objectbenzocoumarin. Suitable DMG to serve as a carboxyl precursor aresecondary and tertiary amides and oxazolino groups. Specifically theseprecursors may be, for example, --CONEt₂, --CONHMe,4,4-dimethyl-2-oxazolinyl, and the like. In the instance of compoundA1-1, DMG is of the carboxyl precursor type. Suitable DMG to serve as aphenolic precursor are carbamates and ethers. Specifically, theseprecursors may be O-methoxymethyl (OMOM), OMe, OCONEt₂,2-(trimethylsilyl)ethoxymethoxy (OSEM) and the like. Compound A2-1 asdescribed below is by way of example, of the phenolic precursor type.

As the first step of flow Sheet A1, the bromine of compound A1-1 isprotected through silylation via halogen metal exchange in the presenceof trimethylsilyl chloride (TMS-C1) at between about -100° to -50° C. toproduce aryl silane A1-2. Incorporation of an ortho substituent R^(a) orits appropriate precursor may be made on compound A1-2 in accordancewith standard directed metalation procedures described by Snieckus, etal., above. The resultant substituted aryl silane A1-3 is iterativelyortho metalated and treated with an appropriate boron containingelectrophile to obtain the requisite aryl boronic acid A1-4. Suitableboron containing electrophiles include lower alkyl borates, such astrimethyl borate and tri-i-propyl borate. Alternatively, and not shownin the Flow Sheets, the ortho metalated compound may be treated withelectrophiles such as trialkyltin halides providing the correspondingaryl stannanes which in turn are also useful intermediates in theproduction of biphenyls as reported by Stille, et al., J. Am. Chem.Soc., 1987, 109, 5478-5486. Preparation of biphenyl intermediate A1-6 isaccomplished in the Flow Sheets utilizing the Suzuki cross-couplingprocedure and the appropriately adorned aryl compounds A1-4 and A1-5.The Suzuki coupling can be generally described as the reaction of anaryl boronic acid with an aryl halide or halide equivalent employingtetrakis(triphenylphosphine) palladium(O) catalyst in the presence of anaqueous solution of sodium carbonate in the solvents toluene/ethanol.The resulting biphenyl compound is isolated by standard methods.Compound A1-5 may itself be produced by standard methods to obtain thehalogen substitution, X", the phenolic moiety, --OR', and the desiredsubstituents R^(a) or their precursors. The preferred halogen X" isbromine, iodine or the halogen equivalent trifluoromethanesulfonyloxy.The preferred phenolic moiety, --OR', may be any of the oxygen basedDMGs described above, or a suitably protected phenol where theprotecting group is not a DMG. Biphenyl compound A1-6 is subsequentlytransformed into the halogenated biphenyl A1-7 via ipso substitution ofthe trimethylsilyl moiety in methylene chloride or other appropriatesolvent employing iodine monochloride. Any number of halogenatingreagents are suitable, such as IBr, NBS, I₂, Br₂, etc., which must becompatible with the already existing functionalities. Finally, theobject compound, B1-1, is obtained via lactonization of the phenolicmoiety with the latent carboxy precursor in the form of DMG.

Referring to Flow Sheet A2, the regioisomeric benzocoumarin B1-2, may beproduced in a manner analogous to that of benzocoumarin B1-1. CompoundA2-1 is dissimilar to compound A1-4 in that DMG of compound A2-1 is ofthe phenolic precursor type. Compound A2-1 is reacted with theappropriately adorned compound A2-2 to prepare biphenyl intermediateA2-3 utilizing the Suzuki cross-coupling procedure. As above biphenylcompound A2-3 is transformed into halogenated biphenyl via ipsosubstitution on A2-4 and finally into object benzocoumarin B1-2 vialactonization.

Presented with Flow Sheet A1 and A2, the skilled artisan will appreciatecertain modifications as possibly beneficial. In one modification, theipso substitution of silicon to halogen might be performed aftercyclization to form the object benzocoumarin. In another modification,compounds A1-5 and A2-2 may be adorned utilizing a DMG substituentreplacing --OR' and --CO₂ Me respectively. As above, the DMG substituentdirects adornment of R^(a) or precursors thereof in manufacture. Asabove, the DMG should be of the carboxyl precursor type or phenolicprecursor type as appropriate. In yet another modification, theoxocarbonyl of intermediate B1-1 or B1-2 can be converted to athiocarbonyl to produce X^(h) as S using Lawesson type reagents or bytreating with phosphorus pentasulfide in an appropriate solvent. Anothermodification to produce X^(h) as S is to employ a carbon based DMGwherein the oxocarbonyl moiety is replaced by thiocarbonyl. A suitablecarbon based DMG containing thiocarbonyl is --(C═S)NH-phenyl. Althoughcompounds in which X^(h) is S are suitable, compounds in which X^(h) isO are preferred.

Although the foregoing method to produce benzocoumarins B1-1 or B1-2 ispreferred herein, there are of course other appropriate methods. Forexample, the method of F. F. Abdel-Latif, Gazz. Chim. Ital., 1991, 121,9-10, to produce benzocoumarins may be modified by subsequentbromination or by bromine substitution on starting materials to obtainthe benzocoumarin required herein. Methods cited in the review by G.Brigmann, et al., Angew. Chem. Int. Ed. Eng., 1990, 29, 977-991, or themethod of Jung, M. E., et al., Tetrahedron Lett., 1988, 29, 2517-2520,or that of Deshpande, P. P., et al., Tetrahedron Lett., 1990, 31,6313-6316 may also be employed. ##STR15##

The object compound of Flows Sheet A1 and A2, benzocoumarin B1-1 andB1-2, forms the nucleus of the 2-position substitution of the carbapenemcompounds taught herein. As such it is shown to be R^(a) substituted.However, it is immediately clear to those skilled in the art thatcertain R^(a) listed above, if substituted on compounds A1-1, A1-5, A2-1or A2-2 would not survive or permit the synthesis to compounds B1-1 orB1-2. Thus, where a certain R^(a) is desired on compound B1-1 or B1-2and this R^(a) is not compatible with the synthesis scheme to produce,B1-1 or B1-2 then a compatible precursor substituent may be employedthrough the synthesis.

The identity of the precursor substituent employed is not crucial solong as it does not interfere with the synthesis to B1-1 or B1-2 and solong as it may be thereafter converted to a more desireable substituent.Preferred precursor substituents for R^(a) are methyl, hydroxymethyl andprotected hydroxymethyl.

Thus, as to the R^(a) substituent on compound B1-1 or B1-2, it may be anR^(a) with or without protecting groups stable to the conditions ofproducing compound B1-1 or B1-2, and stable to the conditions ofsubsequently adding B1-1 or B1-2, to the carbapenem. Alternatively, itmay be a stable precursor substituent which is stable to the conditionsof making B1-1 or B1-2, which is optionally stable to the conditions ofadding B1-1 or B1-2, to the carbapenem and which is convertible to adesired R^(a) or to another precursor substituent.

As stated above, the second stage synthesis is to attach the basebenzocoumarin B1-1 or B1-2 to the 2-position of the carbapenem. Onemethod to attach B1-1 or B1-2 to the base carbapenem utilizes theGrignard reaction. By this method however, B1-1 and B1-2 cannot beemployed as such. Instead, the benzocoumarin precursor, i.e. thebiphenyl, is employed as the Grignard reagent in the second stagesynthesis. Thus, in this method, employing the Grignard reaction, thefirst stage synthesis, described above, is completed in the second stagesynthesis. With stable R^(a) or suitable precursor substituentstherefor, biphenyl A1-7 may be added to azetidin-2-one B2 in a Grignardreaction as shown in Flow Sheet B. In a similar manner, biphenyl A2-4may also be added where the methyl ester moiety has first beensaponified to the acid. The Grignard reaction required that A1-7, forexample, be converted to a Grignard reagent by reaction with magnesiumand 1,2-dibromoethane in THF from 20° C. to 60° C. and subsequentlycontacting A1-7 as a Grignard reagent with B2 in THF at from -70° C. toabout 20° C. to produce azetidin-2-one B3. Alternatively, B1-1 may bereacted with t-butyl-lithium, n-butyllithium, or the like in THF at from-78° C. to -50° C. followed by the addition of magnesium bromide toproduce the same Grignard reagent. R^(i) of B3 is in practice pyrid-2-ylbut may clearly be a variety of substituents including aromatic andheteroaromatic substituents. Further R^(i) might be for example phenyl,2-pyrimidinyl or 2-thiazolyl. Subsequently to this Grignard reaction,the biphenyl moiety is transformed to a benzocoumarinyl platform aspreviously described to produce B4.

Azetidin-2-one B4 is an intermediate that may be ring closed to acarbapenem. It is on this intermediate that R^(a) or precursorsubstituents may be modified where such modification is incompatiblewith the carbapenem nucleus.

Compound B4 may be ring closed to carbapenem B5 by refluxing in xylenewith a trace of p-hydroquinone for about 1 to 2 hours in an inertatmosphere. It is on this intermediate that final elaboration of R^(a)from a precursor substituent, e.g. hydroxymethyl, may be accomplished.Removal of the carboxyl and hydroxyl protecting groups then provides thefinal compound of Formula I. Such final elaboration and deprotection isdescribed in further detail below. ##STR16##

Flow Sheet C shows an alternative preferred second stage synthesis, i.e.attachment of the base benzocoumarin such as B1-1 to the 2-position ofthe carbapenem. This synthesis involves a palladium catalyzedcross-coupling reaction between a carbapenem triflate and a suitablysubstituted arylstannane, a process which is described in U.S. patentapplication Ser. No. 650,011 filed Feb. 04, 1991, hereby incorporated byreference. In order to apply this synthesis, it is first necessary tomodify benzocoumarin B1-1 to the trimethylstannylbenzocoumarin C3. Thisis accomplished by reacting benzocoumarin B1-1 with hexamethylditin inthe presence of a palladium(O) catalyst such astetrakis(triphenylphosphine)palladium(O) in an inert solvent such astoluene at from 25° to 110° C. for from 0.25-24 hours to provide thestannane C3. Referring to Flow Sheet C, the 2-oxocarbapenam C1 isreacted with a suitable trifluoromethanesulfonyl source, such astrifluoromethanesulfonic anhydride, in the presence of an organicnitrogen base, such as triethylamine, diisopropylamine and the like, inpolar aprotic solvent, such as tetrahydrofuran or methylene chloride.Optionally, an organic nitrogen base, such as triethylamine and thelike, is then added to the reaction solution followed immediately by asilylating agent, such as trimethylsilyl trifluoromethanesulfonate toprovide intermediate C2. An aprotic polar coordinating solvent, such asDMF, 1-methyl-2-pyrrolidinone and the like, is optionally added. This isfollowed by the addition of a palladium compound, such astris(dibenzylideneacetone)dipalladium-chloroform, palladium acetate andthe like, optionally, a suitably substituted phenylphosphine, such astris(4-methoxyphenyl)phosphine, tris(2,4,6-trimethoxyphenyl)phosphineand the like, and the stannane C3. A halide source, such as lithiumchloride, zinc chloride or ammonium chlorides and the like, is added andthe reaction solution is allowed to warm and is stirred at a suitabletemperature, such as 0° to 50° C. for from a few minutes to 48 hours.The carbapenem C4 is obtained by conventional isolation/purificationmethodology known in the art.

Generally speaking, the milder conditions of the synthesis shown in FlowSheet C allow for a wider range of functional groups R^(a) to be presentthan the synthesis illustrated in Flow Sheet B. However, in certaincases it is advantageous for the R^(a) substituent(s) of the stannane C3to be introduced in a protected or precursory form. Final elaboration ofR^(a) from a precursor substituent, e.g. hydroxymethyl, may beaccomplished on carbapenem intermediate C4. Removal of hydroxyl andcarboxyl protecting groups then provides the final compound of FormulaI. Such final elaboration and deprotection is described in furtherdetail below. ##STR17##

Azetidin-2-one B2, a pyridyl-thioester, is a well known compound in theproduction of carbapenems. Diverse synthetic schemes useful to make B2may be imagined by the skilled artisan. Particularly useful to theinstant invention is a synthetic scheme set out further in Flow Sheet Dbelow in which the symbol R is as defined above. The steps for preparingintermediate B2 are analogous to the procedures described, for example,in U.S. Pat. Nos. 4,260,627 and 4,543,157; L. D. Cama et al. Tetrahedron39, 2531 (1983); R. N. Guthikonda et al. J. Med. Chem., 30, 871 (1987)hereby incorporated by reference. ##STR18##

The steps for preparing the 2-oxocarbapenam intermediate C1 are wellknown in the art and are explained in ample detail by D. G. Melillo etal., Tetrahedron Lett., 1980, 21, 2783, T. Salzmann et al., J. Am. Chem.Soc., 1980, 102, 6161, and L. M. Fuentes, I. Shinkai, and T. N.Salzmann, J. Am. Chem. Soc., 1986, 108, 4675. The syntheses are alsodisclosed in U.S. Pat. No. 4,269,772, U.S. Pat. No. 4,350,631, U.S. Pat.No. 4,383,946 and U.S. Pat. No. 4,414,155 all assigned to Merck andCompany, Inc. and hereby incorporated by reference.

The general synthesis description depicted above in the Flow Sheetsshows a protected 1-hydroxyethyl substitutions on the 6-position of thecarbapenem. After final deprotection, a 1-hydroxyethyl substituent isobtained, which is preferred in most cases. However, it has been beenfound that with certain 2-side-chain selections, the ultimate balance offavorable properties in the overall molecule may be enhanced byselection of the 6-(1-fluoroethyl) moiety instead. Preparation of6-fluoroalkyl compounds within the scope of the present invention iscarried out in a straightforward manner using techniques well known inthe art of preparing carbapenem antibacterial compounds. See, e.g., J.G. deVries et al., Heterocycles, 1985, 23, 1915; BE 900 718 A (Sandoz)and Japanese Patent Pub. No. 6-0163-882-A (Sanraku Ocean).

In the compounds of the present invention, one of the R^(a) substituentsmust be of Type I. As a general matter, it is conjectured thatanti-MRSA/MRCNS activity results from the configuration of the overallmolecule uniquely conferred by the benzocoumarin nucleus. The Type Isubstituent provides still greater anti-MRSA/MRCNS activity to themolecule.

The Type II R^(a) substituents are distinguishable from Type Isubstituents chemically and with respect to the biological propertieswhich they confer. In related compounds, it has been found that the TypeII substituted compounds afford greater water solubility and reducedpotential for CNS side effects. Substituents which tend to conferimproved water solubility on the overall compound have been founduseful, since they are contemplated to thereby improve the transport ofthe compound involved. Although a substantial number and range of TypeII substituents have been described herein, all of these arecontemplated to be a part of the present invention based on thebiological performance of substituents related in terms of theirmedicinal chemistry.

Since it is possible to combine, in the compounds of the presentinvention, the required Type I substituents with the optional Type IIsubstituents, there can be obtained a combination of desired attributesin the final overall molecule not attainable with a single substituent,i.e., improved anti-MRSA/MRCNS activity together with enhanced watersolubility.

Type I substituents employed in the compounds of the present inventionmay have quaternary nitrogen groups, and these include both cyclic andacyclic tapes, as is described under Type I. As already pointed outabove, it is required that one, but no more than one, of thesubstituents R^(a) must be a member selected from the group consistingof the definitions under Type I. It is optional that one, or at mostthree, of the remaining substituents may be a member selected from thegroup consisting of definitions under Type II. For example, R^(a) at the3-position may be Type I and R^(a) at the 7-position may be of Type II,while the remaining substituents are hydrogen.

In preferred compounds of Formula I, R¹ is hydrogen. More preferably, R¹is hydrogen and R² is (R)--CH₃ CH(OH)-- or (R)--CH₃ CH(F)--. In the mostpreferred case, R¹ is hydrogen and R² is (R)--CH₃ CH(OH)--. While R=H isusually preferred, there are instances in which R=CH₃ may provideimproved chemical stability, water solubility, or pharmacokineticbehavior. The substituent R=CH₃ may be of either configuration, i.e.,the α or β-steroisomer. Additionally, in preferred compounds, at leastR^(a) in the 3-, 4- or 7-position of the benzocoumarin is other thanhydrogen. In the most preferred compounds, in total, two R^(a)substituents are other than hydrogen.

Preferred Type I

a) substituents include: ##STR19## where X=O, S, or NR^(c). Forstructures of Type I. a), where R^(c) is shown to have an indefiniteposition, it may be attached to any carbon of the ring.

Preferred Type I

b) substituents include: ##STR20## where X=O, S, or NR^(c) and X'=O orS. For structures of Type I. b), where R^(c) and/or A' are shown to haveindefinite positions, they are independently attached to any carbon atomof the ring.

Preferred Type I

c) substituents include: ##STR21## where W is O, S, NR^(e), N(O)R^(e),SO, SO₂ or N⁺ (R^(e))₂ and W' is N⁺ R^(e) or NO. For structures of TypeI. c), where R^(q) is shown to have an indefinite position, it may beattached to any carbon atom of the ring.

Preferred Type I

d) substituents include: ##STR22## For structures of Type I. d), whereR^(q) and/or A'_(p) is shown to have an indefinite position, it may beattached to any carbon atom of the ring.

The R^(c) substituents herein are intended to represent suitable furthersubstituents on the Type I. a) or b) substituents for thebenzocoumarinyl ring. As seen above, these Type I. a) or b) substituentsare monocyclic or bicyclic aromatic groups containing heteroatoms. Giventhis class of primary substituent, further suitable substituents may bereadily discovered in the penem and carbapenem art. For example,suitable substituents for Type I. a) or b) substituents are generallytaught in U.S. Pat. No. 4,729,993 assigned to Merck and Co. or in U.S.Pat. No. 4,746,736 assigned to Bristol-Myers Co. These patents arehereby incorporated by reference.

Broadly, R^(c) may be the same or different and may be selected on anindependent basis from the group as defined above. While a single suchsubstitution is preferred, there is occasion to use up to two suchsubstituents on an R^(a), e.g., where it is desired to enhance theeffect of a particular substituent group by employing multiplesubstituents. The particular choice of R^(c) will depend upon thesituation. For instance, a specific R^(c) may lend particular stabilityto a nitrogen cation. At other times it may be desired to employ asubstituent known to enhance antibacterial activity of the overallmolecule against a particular bacterium, for example, while alsoemploying a substituent known to improve some other property such aswater solubility or the duration of action of the overall molecule.

The scope of R^(c) herein includes two specific Types of furthersubstituent attached to the Type I. a) or b) substituent. A first Typeof R^(c) are those attached to a ring carbon and a second Type of R^(c)are those attached to a neutral ring nitrogen. Persons skilled in theart will readily recognize that a wide range of organic substituents aresuitably used as R^(c). Persons skilled in the art will also recognizethat some substituents including the --NR^(y) R^(z) substituents, usefulfor one purpose of R^(c), i.e. carbon substitution, are not equallyuseful in the other, i.e. nitrogen substitution.

Preferred R^(c) attached to ring carbon atoms are --NH₂, --SCH₃,--SOCH₃, --CH₂ OH, --(CH₂)₂ OH, --OCH₃, --COOM^(b), --CH₂ COOM^(b),--CH₂ CH₂ COOM^(b), --CH₂ SOCH₃, --CH₂ SCH₃, --SO₃ M^(b), --CH₂ SO₃M^(b), --CH₂ CH₂ SO₃ M^(b), --Br, --Cl, --F, --I, --CH₃, CH₂ CH₃, CH₂CONH₂ and CH₂ CON(C₁ -C₄ alkyl) where M^(b) is defined above. PreferredR^(c) attached to neutral ring nitrogen atoms are --H, --CH₂ OH,--(CH₂)₂ OH, --CH₂ COOM^(b), --CH₂ CH₂ COOM^(b), --CH₂ SOCH₃, --CH₂SCH₃, --CH₂ SO₃ M^(b), --CH₂ CH₂ SO₃ M^(b), --CH₃, --CH₂ CH₃, --CH₂CONH₂ and --CH₂ CON(C₁ -C₄ alkyl) where M^(b) is defined above.

It is preferred that each Type I. a) or b) substituent have no more thantwo R^(c) substituents which are other than hydrogen. Thus, the formulashown above for Type I. a) substituents has up to two R^(c) substituentswith the remainder of course being hydrogen. Further, the formula forthe Type I. b) substituent also allows up to two R^(c). In accordancewith these formulae, the previously listed more specific structuresshould be interpreted to have no more than two R^(c) for each monocyclicor bicyclic group. Similarly for Type I. c) or d) substituents it ispreferred that any monocyclic or bicyclic group have no more than asingle R^(q) substituent.

The scope of R^(d) includes a single type of further substituentattached a Type I. b) or d) substituent. The R^(d) substituents areattached to a cationic nitrogen which may or may not be aromatic.Preferred R^(d) attached to cationic nitrogen atoms are hydrogen, --CH₃,CH₂ CH₃, --CH₂ CH₂ CH₃, --CH₂ COOM^(b), --CH₂ SO₃ M^(b), --NH₂ andO.sup.(-), where M^(b) is defined above.

The formulas depicting Type Ia, Ib, Ic, and Id substituents showpositively charged states for those substituents. It is understood thatcertain of those substituents, which are cationic by virtue of having aprotonating hydrogen atom attached to a nitrogen atom, may also exist orbe produced under certain conditions as a neutral substituent by virtueof the absence of such a hydrogen atom (i.e. in Type Ib, when there isno R^(d) ; in Type Ic, when there is no R^(w) ; and in Type Id, whenthere is zero to one R^(d), depending on Type of heterocycle). Whethersuch a Type Ia, Ib, Ic, or Id substituent will be predominately cationicor neutral in a given physical state will be governed by principles ofacid-base chemistry, which are well known to those skilled in the art.For example, the particular ratio of neutral form to cationic form willdepend upon the basicity of the amine and acidity of a solution. Whensuch a substituent is in a protonated quaternized state, the compoundexists as a zwitterion which is internally balanced as to charge or asan ammonium salt which is externally balanced. In illustration, if thereis no R^(d) on a Type Ib substituent, it is understood that such asubstituent is neutral (there is no positive charge on the nitrogen). Acompound containing such a substituent is typically produced in thisform as a salt, wherein M is an alkali metal, and may exist in solutionin its neutral form. However, depending upon conditions, a compoundcontaining a neutral Type Ib substituent may be in equilibrium with, andmay also be represented by a formula showing, the corresponding compoundcontaining the quaternized protonated substituent where R^(d) is presentand is a hydrogen atom. Furthermore the same compound may exist with theType Ib substituent in a completely protonated quaternized form, forinstance in an aqueous solution in the presence of a stoichiometricamount of a strong mineral acid. It is intended herein that both theprotonated (cationic) and the unprotonated (neutral) forms of Type Ia,Ib, Ic and Id substituents of the type just described are within thescope of the present invention.

Suitable A space moieties include --CH₂ --, --CH₂ CH₂ --, --CH₂ CH₂ CH₂--, --CH₂ CH₂ CH₂ CH₂ --, --OCH₂ CH₂ --, --SOCH₂ --, --CO₂ CH₂ --,--SCH₂ CH₂ --, --SOCH₂ CH₂ --, --SO₂ CH₂ CH₂ --, --NHCH₂ CH₂ --,--N(CH₃)CH₂ CH₂ --, --CH₂ N(CH₃)CH₂ CH₂ --, --CONHCH₂ CH₂ --, --SO₂NHCH₂ CH₂ --, --COCH₂ --, --CH═CHCH₂ --and --CH₂ OCH₂ CH₂ --.Preferably, where Q is O, S, NH or N(C₁₋₄ alkyl), then n is 2-6.

Suitable A' are listed for A above. Further A' may suitably be --O--,--S--, --NH--, --SO₂ --, --SO₂ NH--, --CONH--, --CH═CH--, --CH₂ S--,--CH₂ NH--, --CONHCH₂ -- or --SO₂ NHCH₂ --.

The Type I, cationic substituents are generally added to thebenzocoumarin following attachment of the benzocoumarin to thecarbapenem. Conveniently, the benzocoumarin side-chain should besynthesized with precursor substituent which may be elaborated into thedesired cationic substituent. The identity of the precursor substituentwill vary according to the particular R^(a) desired. For example, onesuch precursor substituent is --A--OH, such as hydroxymethyl.

The hydroxymethyl precursor substituent may be elaborated into cationicsubstituents of Type I.a) by converting the hydroxyl into an activeleaving group such as an iodide (giving --A--I) followed by reactionwith a desired nitrogen containing aromatic compound. More particularly,two alternative procedures may be utilized to produce a leaving group onthe moiety --A-- and subsequently to replace such a leaving group withcationic substituents of the type just described.

For a first procedure, the hydroxyl group of --A--OH may be converted toa methanesulfonate group by treating with methanesulfonyl chloride inthe presence of triethylamine. A suitable solvent, e.g.,dichloromethane, is employed and the reaction is carried out at reducedtemperatures. In turn, the methanesulfonate intermediate which itself isa good leaving group may be converted to the reactive iodide derivativeby treatment with sodium iodide in a suitable solvent, e.g., acetone, atreduced or ambient temperatures. Alternatively, the hydroxyl group maybe directly converted into the iodide group by common methods known tothe art. For example, treatment of the hydroxyl group with methyltriphenoxyphosphonium iodide in a suitable solvent, such asdimethylformamide, at reduced or ambient temperatures, directly providesthe desired iodide. Once the iodide has been formed, the introduction ofthe cationic substituent is accomplished simply by treating the iodidewith the desired nitrogen containing compound, e.g. a heteroaromaticcompound such as pyridine. The reaction will proceed in a suitablesolvent, such as acetonitrile, at or about room temperature. Thisdisplacement reaction may also be facilitated by the addition of excesssilver trifluoromethanesulfonate to the reaction mixture, in which casereduced temperatures are often desirable.

For a second procedure, the hydroxyl group of --A--OH may be convertedinto the reactive trifluoromethanesulfonate (triflate) group. However,such an activating group cannot be isolated by conventional techniquesbut may be formed and use in situ. Thus, treatment of the hydroxyl groupwith trifluoromethanesulfonic (triflic) anhydride in the presence of ahindered, non-nucleophilic base such as 2,6-lutidine, 2,4,6-collidine,or 2,6,-di-tert-butyl-4-methylpyridine in a suitable solvent, such asdichloromethane, at reduced temperatures provided for the generation ofthe triflate activating group. Introduction of the cationic group isthen accomplished by reacting the above triflate in situ with thedesired nitrogen containing compound at reduced temperature. In certaincases it is possible and desirable to use the reacting nitrogencontaining compound as the base for the formation of the triflateactivating group. In this case treatment of the hydroxyl group withtriflic anhydride in the presence of at least two equivalents of thereacting nitrogen compound under the conditions described above providesthe cationic substituent.

The above are representative of suitable leaving groups:alkylsulfonyloxy, substituted alkylsulfonyloxy, arylsulfonyloxy,substituted arylsulfonyloxy, fluorosulfonyloxy and halogen. The commonsulfate leaving groups are: methanesulfonyloxy,trifluoromethanesulfonyloxy, fluorosulfonyloxy, p-toluenesulfonyloxy,2,4,6-tri-isopropylbenzenesulfonyloxy, p-bromobenzenesulfonyloxy andp-nitrobenzenesulfonyloxy. The preferred halo leaving groups are bromoand iodo. These alkyl and arylsulfonate leaving groups may be preparedusing an analogous route to the one described above using the sulfonylchloride or the sulfonic anhydride.

Where the cationic substitution has a substituent R^(c), the most facilemethod of providing such a substituent is to employ as the reactant inthe preparation methods described above a nitrogen containing compoundwhich already has the desired substituent. Such substituted compoundsare readily available starting materials or may be prepared in astraight-forward manner using known literature methods.

The Type I.b) cationic substituents are prepared by quaternization of anaromatic ring nitrogen of a neutral precursor substituent on thebenzocoumarin ring. Examples of neutral precursor substituents are--CONHCH₂ --(2-pyridyl), --CONHCH₂ --(4-pyridyl) or --SO₂ CH₂--(4-pyridyl). Quaternization is accomplished by reacting the nitrogencompound in an inert organic solvent (e.g. CH₂ Cl₂) at about 0° C. toroom temperature with an alkylating agent R^(d) --Y where R^(d) is givenabove and Y is a leaving group such as iodide, bromide, mesylatemethanesulfonate), tosylate (p-toluenesulfonate) or O-triflate.Alternatively, the aromatic ring nitrogen may be quaternized by reactionwith an ozidizing agent such as 3-chloroperbenzoic acid (giving theN-oxide) or an amidinating reagent such aso-(2,4,6-triisopropylbenzenesulfonyl)hydroxylamine (giving the N-aminoderivative) in a suitable solvent (e.g. dichloromethane or CH₃ CN) atabout room temperature. In addition, the neutral precursor substituentmay be rendered cationic through protonation of the basic aromatic ringnitrogen. This may be accomplished by treatment of the neutral precursorwith a suitable inorganic or organic acid, e.g., hydrochloric acid,phosphoric acid, hydrobromic acid, acetic acid or benzoic acid.Protonation may further be accomplished by a carboxylic acid functionelsewhere in the molecule, including the C-3 carboxyl on the carbapenem.The neutral precursor substituent may be already attached to thebenzocoumarin ring at the time of its connection to the carbapenem, orit may be elaborated from a simpler precursor after connection to thecarbapenem. An example of a precursor substituent for elaboration is--A'--OH such as hydroxymethyl. In one suggested synthesis, the hydroxylmay be converted to a reactive leaving group such as iodo as describedabove. The iodide is then reacted in a nucleophilic displacementreaction with a nitrogen containing aromatic compound which has anucleophilic side-chain substituent such as CH₂ SH or CH₂ NH₂. In thisdisplacement reaction, it is the side-chain substituent that is thereacting nucleophile and not the aromatic ring nitrogen. Suitablesubstrates for this reaction include 2-(mercaptomethyl)pyridine,2-aminopyridine, 2-(aminomethyl)pyridine or 4-(mercaptomethyl)pyridine.The reaction is carried-out in an inert organic solvent, e.g., methylenechloride, at from about 0° C. to room temperature in the presence of anon-nucleophilic base such as triethylamine or diisopropylethylamine.Quaternization or protonation of the aromatic ring nitrogen as describedabove then gives the Type I.b) cationic substituent. A second suggestedsynthesis of a Type I.b) cationic substituent starting from a precursor--A'--OH (e.g. hydroxymethyl) consists of oxidation of the alcoholfunctionallity to an aldehyde followed by Wittig-type olefination withan appropriate nitrogen-containing aromatic substituted reagent, andfinally quaternization. The oxidation may be conveniently accomplishedby a Swern oxidation employing oxalyl chloride-dimethylsulfoxidefollowed by triethylamine. The reaction is conducted in methylenechloride as a solvent at from --70° C. to 0° c. The Wittig reaction iscarried-out by reacting the aldehyde with the desired Wittig reagent ina polar solvent such as acetonitrile or dimethylsulfoxide at about roomtemperature. Suitable Wittig reagents include:pyridylmethylenetriphenylsphosphorane,quinolylmethylenetriphenylphosphorane, andthiazolylmethylenetriphenylphosphorane. Quaternization or protonation asdescribed above then completes the synthesis of the Type I.b) cationicsubstituent. Depending on the particular R^(a) of Type I.b) that isdesired, many other synthesis schemes may be employed, as would beapparent to an organic chemist skilled in the art.

The type I.c) cationic substituents may be prepared in an analogousmanner to that described for I.a) substituents except that the nitrogencontaining compound employed in the displacement reaction is analiphatic amine (i.e. NR^(y) R^(z) R^(w)). However, in cases where theamino group is directly bonded to the benzocoumarin nucleus (i.e.--A_(p) N⁺ R^(y) R^(z) R^(w) where p=0) the amine is most convenientlyattached to the benzocoumarin prior to its incorporation into thecarbapenem system. If such an amine is primary or secondary, it mayrequire protection with a suitable amine protecting group during thesteps employed to attach the benzocoumarin to the carbapenem. Tertiaryamines require no protection and may be quaternized or protonated asdescribed for the Type I.b) cationic substituents.

The Type I.d) cationic substituents are prepared by quaternization orprotonation of a non-aromatic ring nitrogen of an appropriate neutralprecursor substituent on the benzocoumarin ring. Quaternization orprotonation is accomplished as described above for the Type I.b)substituents. As with the Type I.b) substituents, the neutral precursormay already be attached to the benzocoumarin ring at the time of itsconnection to the carbapenem, or the neutral precursor may be elaboratedfrom a simpler precursor substituent on the benzocoumarin ring after itsconnection to the carbapenem. Examples of neutral precursor substituentsare: --CONH(3-quinuclidinyl), --CONH[4-(N-methylpiperidinyl], --SO₂ CH₂CH₂ [2-(N-methylpyrrolidinyl]. --SO₂ NH[1-(4-methylpiperazinyl] and--CH₂ [1-(4-methylpiperazinyl]. Elaboration of the neutral precursorsubstituent from a simpler substituent such as hydroxymethyl may beaccomplished in an analogous manner to that described previously for theType I.b) substituents by employing appropriate reagents to introducethe Type I.d) non-aromatic ring nitrogen moiety which is subsequently tobe quaternized or protonated.

It should be clear that for any of the Type I.a) to I.d) substituents,that the substituent may be suitably formed on the benzocoumarin priorto addition to the carbapenem. Thus, the substituent may be formed on C3and reacted with C2 to form the protected carbapenem C4. For example,3-hydroxymethyl-9-trimethylstannylbenzocoumarin, i.e. C3, may besubstituted by reaction with triflic anhydride and N-methylimidazole ina suitable solvent, such as, dichloromethane under nitrogen at -78° C.to room temperature to form a Type I.a) substituted benzocoumarin, i.e.C3. This substituted benzocoumarin may be reacted with C2 employingconditions otherwise described herein and specifically using an ammoniumchloride source.

Suitable R^(a) are described above in the text associated with FormulaI. Among preferred R^(a) of Type II are C₁₋₄ alkyl mono-substituted withhydroxy, such as, hydroxymethyl; formyl; alkoxycarbonyl, such as,--COOCH₃ ; carbamoyl, such as, --CONH₂ ; hydroximinomethyl, such as,--CH═NOH; or cyano.

In regard to this preferred substitution, a hydroxymethyl may beobtained in any of positions 7, 1, 2, 3 or 4 for R^(a) as follows. Asone method, hydroxymethyl may be substituted on any of rings A1-4 andA1-5 or A2-1 and A2-2 by standard procedures and appropriatelyprotected. Alternatively, methyl, as a precursor substituent, issubstituted on starting materials A1-4 and A1-5 or A2-1 and A2-2 in theappropriate positions by well known means and the starting materialsreacted to a corresponding methyl-substituted B1-1 or B1-2 according toFlow Sheet A1 or A2 respectively. Subsequently, the methylsubstituent(s) of methyl substituted B1-1 or B1-2 may be oxidized tobromomethyl with N-bromosuccinimide. This oxidation of the precursorsubstituent, methyl, is advantageously performed prior to substitutingthe benzocoumarin on the azetidin-2-one as the oxidizing conditions areincompatible with either the azetidin-2-one or the subsequentcarbapenem. In the case of the bromomethyl substituent, conversion to anhydroxymethyl substituted B1-1 or B1-2 may be accomplished by athree-step sequence. Reaction of the bromomethyl compound with potassiumacetate in DMF at 80° C. gives the corresponding acetoxymethyl compound.Removal of the acetate group, e.g. by hydrolysis with methanolic sodiumhydroxide or by reduction with diisobutylaluminium hydride in THF, givesthe hydroxymethyl substituted compound B1-1 or B1-2. Further elaborationof hydroxymethyl substituted A1-7 or A2-4 according to Flow Sheet Bproduces a corresponding B4 and B5.

The preferred formyl substitution on the benzocoumarin may be obtainedon B5 from the hydroxymethyl substitution, in the case of R^(a), by aSwern oxidation. For example, B5 is oxidized in methylene chloride atfrom -70° C. to room temperature employing oxalyl chloride-dimethylsulfoxide followed by triethylamine as the active agent. Obviously, theposition of the resultant formyl substitution will depend upon theposition of the hydroxymethyl substitution on B5.

The preferred --CH═NOH substitution on the benzocoumarin may beconveniently obtained from the formyl substitution just described. Thisis accomplished simply by exposing the formyl substituted compound tohydroxylamine in an appropriate solvent at room temperature.

The preferred cyano substitution on the benzocoumarin may be obtainedfrom the --CH═NON substitution just described. The --CH═NOH substitutedcompound is dehydrated with triflic anhydride and triethylamine in asolvent at -70° C.

The --COOCH₃ substitution on the benzocoumarin may be obtained from thehydroxymethyl substituted B4 described above. For example, compound B4is oxidized with Jones reagent to convert the hydroxymethyl substituentto the carboxylic acid group. The oxidation with Jones reagent may beincompatible with the carbapenem and thus is optimally performed beforering closure. Prior to ring closure, the carboxylic acid group isesterified by sequentially contacting with1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride,1-hydroxybenzotriazole, and methanol in an organic solvent at roomtemperature. Substituted esters may of course be obtained by replacingmethanol with the corresponding substituted alcohol. Alternatively, amethyl substituted B1-1 or B1-2, as described above, may be oxidizedwith chromium trioxide or ^(n) Bu₄ NMnO₄ to form carboxy.

The preferred carbamoyl substitution on the benzocoumarin, may beobtained from B3 or B4 by oxidizing the hydroxymethyl group with Jonesreagent to the corresponding carboxylic acid group as described above.This carboxylic acid substituent is converted to the carboxamide group,--CONH₂, by sequentially contacting with1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,1-hydroxybenzotriazole, and ammonia in an organic solvent at roomtemperature. Substituted amides may of course be obtained by replacingammonia with the corresponding substituted amine. In contrast to thecarboxyl substitution, this carbamoyl group requires no protection forthe conditions of carbapenem cyclization.

Compounds substituted with the preferred R^(a) of Type II just describedmay also be obtained by employing the synthesis shown in Flow Sheet C.In this case, the synthetic transformation just described may becarried-out on intermediate B1-1 or C3 prior to attachment of thebenzocoumarin side chain to the carbapenem or on C4 after suchattachment.

In addition to or including the above, suitable R^(a) of Type IIinclude:

    ______________________________________                                        --OCH.sub.3       --OCH.sub.2 CO.sub.2 CH.sub.3                               --OCH.sub.2 CH.sub.2 OH                                                                         --CF.sub.3                                                  --F               --Cl                                                        --Br              --I                                                         --OH              --OCOCH.sub.3                                               --OCONH.sub.2     --SCH.sub.3                                                 --SOCH.sub.3      --SO.sub.2 CH.sub.3                                         --SCH.sub.2 CH.sub.2 OH                                                                         --SOCH.sub.2 CH.sub.2 OH                                    --SO.sub.2 NH.sub.2                                                                             --SO.sub.2 N(CH.sub.3).sub.2                                --NHCHO           --NHCOCH.sub.3                                              --NHCO.sub.2 CH.sub.3                                                                           --NHSO.sub.2 CH.sub.3                                       --CN              --CHO                                                       --COCH.sub.3      --COCH.sub.2 OH                                             --CH═NOH      --CH═NOCH.sub.3                                         --CH═NOCH.sub.2 CO.sub.2 CH.sub.3                                                           --CH═NOCMe.sub.2 CO.sub.2 CH.sub.3                      --CH═NOCMe.sub.2 CONH.sub.2                                                                 --CO.sub.2 CH.sub.2 CH.sub.2 OH                             --CONH.sub.2      --CONHCH.sub.3                                              --CON(CH.sub.3).sub.2                                                                           --CONHCH.sub.2 CN                                           --CONHCH.sub.2 CONH.sub.2                                                                       --CONHCH.sub.2 CO.sub.2 CH.sub.3                            --CONHOH          --CONHOCH.sub.3                                             tetrazolyl        --CO.sub.2 CH.sub.3                                         --SCF.sub.3       --CONHSO.sub.2 Ph                                           --CONHSO.sub.2 NH.sub.2                                                                         --SO.sub.2 CF.sub.3                                         --SO.sub.2 NHCN   --SO.sub.2 NHCONH.sub.2                                     --CH═CHCN     --CH═CHCONH.sub.2                                       --CH═CHCO.sub.2 CH.sub.3                                                                    --C.tbd.C--CONH.sub.2                                       --C.tbd.C--CN     --CH.sub.2 OH                                               --CH.sub.2 N.sub.3                                                                              --CH.sub.2 CO.sub.2 CH.sub.3                                --SO.sub.2 CH.sub.2 CH.sub.2 OH                                                                 --SCH.sub.2 CONH.sub.2 and                                  --CH.sub.2 I.                                                                 ______________________________________                                    

In the preparation methods described above, the carboxyl group at the3-position and the hydroxyl group at the 8-position of the carbapenemremain blocked by protecting groups until the penultimate product isprepared. Suitable hydroxyl protecting groups, P', are silyl groups suchas trialkylsilyl, aryl(alkyl)alkoxysilyl, alkoxydiarylsilyl anddiarylalkylsilyl and carbonate groups such as alkyloxy and substitutedalkyloxycarbonyl, benzyloxycarbonyl, substituted benzyloxycarbonyl,allyloxycarbonyl and substituted allyloxycarbonyl. The preferredprotecting groups, in addition to or including those shown in theschemes, are t-butylmethoxyphenylsilyl, t-butoxydiphenylsilyl,trimethylsiyl, triethylsilyl, t-butyldimethylsilyl,o-nitrobenxyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl,t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl andallyloxycarbonyl. Suitable carboxyl protecting groups M, in addition toor including those shown in the schemes are described herein below.

Deblocking may carried out in a conventional manner. For compoundsprepared according to Flow Sheet B, deprotection may be carried out in apalladium catalyzed reaction in a solution containing potassium2-ethylhexanoate and 2-ethylhexanoic acid or, alternatively, anothersuitable nucleophile such as pyrrolidine. Alternatively, for thoseprepared via Flow Sheet C, deprotection is conducted sequentially. Thus,compound C4 is exposed initially to aqueous acidic conditions, aceticacid or dilute HCl or the like, in an organic solvent such astetrahydrofuran containing some H₂ O at 0° C. to ambient temperature forfrom a few minutes to several hours. The resulting desilylatedcarbapenem may be isolated by conventional techniques, but is moreconveniently taken into the final deprotection process. Thus, additionof an inorganic base such as NaHCO₃ or KHCO₃ and a catalyst such as 10%Pd/C or 5% Al₂ O₃ followed by hydrogenation provides for the removal ofthe p-nitrobenzyl protecting group and the formation of the finalcompound of Formula I.

The overall molecule must be electronically balanced. Since a quaternarynitrogen is present in the compounds of the present invention, abalancing anion must also, in that case, be present. This is usuallyaccomplished by allowing COOM to be COO-. However, where M is, e.g., apharmaceutically acceptable ester, a counterion (anion) Z⁻ must beprovided, or alternatively, an anionic substituent might be utilized. Acounterion must also be provided or additional anionic substituentutilized where there is more than one quaternary nitrogen. Further, itis within the scope of this invention to utilize an anionic substituentwhere the quaternary nitrogen is already balance by COOM=COO⁻. In thatcase, it will be understood that it is necessary to provide a counterion(cation) for the anionic substituent. However, it is well within theskill of a medicinal chemist, to whom there is available many suitableanionic and cationic counterions, to make such choices.

With reference to the above definitions, "alkyl" means a straight orbranched chain aliphatic hydrocarbon radical.

The term "quaternary nitrogen" as used herein refers to a tetravalentcationic nitrogen atom including the cationic nitrogen atom in atetra-alkylammonium group (eg. tetramethylammonium, N-methylpyridinium),the cationic nitrogen atom in a protonated ammonium species (eg.trimethylhydroammonium, N-hydropyridinium), the cationic nitrogen atomin an amine N-oxide (eg. N-methylmorpholine-N-oxide, pyridine-N-oxide),and the cationic nitrogen atom in an N-amino-ammonium group (eg.N-aminopyridinium).

The term "heteroatom" means N, S, or O, selected on an independentbasis.

The term "heteroaryl" has been defined herein, in relation to the R^(x)group, to have a specific and limited meaning, being only monocyclic.While the cationic groups I a) and b) also clearly include hteroarylgroups, being both monocyclic and bicyclic, the term "heteroaryl" hasnot been used in association with the definitions of those cationicgroups above. It is required that the monocyclic heteroaryl have atleast one nitrogen atom, and optionally at most only one additionaloxygen or sulfur heteroatom may be present. Heteroaryls of this type arepyrrole and pyridine (1 N); and oxazole, thiazole or oxazine (1 N+1 O or1 S). While additional nitrogen atoms may be present together with thefirst nitrogen and oxygen or sulfur, giving, e.g., a thiadiazole(2N's+1S), the preferred heteroaryls are those where only nitrogenheteroatoms are present when there is more than one. Typical of theseare pyrazole, imidazole, pyrimidine and pyrazine (2 N's) and triazine (3N's).

The heteroaryl group of R^(x) is always optionally mono-substituted byR^(q), defined above, and substitution can be on one of the carbon atomsor one of the heteroatoms, although in the latter case certainsubstituent choices may not be appropriate.

Listed in Table I are specific compounds of the instant invention:

                                      TABLE I                                     __________________________________________________________________________     ##STR23##                                                                    F or OH, R is H or Me and E is:                                                ##STR24##                                                                    __________________________________________________________________________    M      R.sup.a             Position                                           __________________________________________________________________________    (-)                                                                                   ##STR25##          7                                                  (-)                                                                                   ##STR26##          3                                                  (-)                                                                                   ##STR27##          4                                                  (-)                                                                                   ##STR28##          2                                                  (-)                                                                                   ##STR29##          3                                                  (-)                                                                                   ##STR30##          7                                                  (-)                                                                                   ##STR31##          3                                                  (-)                                                                                   ##STR32##          4                                                  (-)                                                                                   ##STR33##          2                                                  (-)                                                                                   ##STR34##          1                                                  (-)                                                                                   ##STR35##          7                                                  (-)                                                                                   ##STR36##          3                                                  (-)                                                                                   ##STR37##          4                                                  (-)                                                                                   ##STR38##          2                                                  (-)                                                                                   ##STR39##          3                                                  (-)                                                                                   ##STR40##          7                                                  (-)                                                                                   ##STR41##          7                                                  (-)                                                                                   ##STR42##          4                                                  (-)                                                                                   ##STR43##          7                                                  (-)                                                                                   ##STR44##          7                                                  (-)                                                                                   ##STR45##          3                                                  (-)                                                                                   ##STR46##          4                                                          ##STR47##          4                                                  (- )                                                                                  ##STR48##          3                                                  K                                                                                     ##STR49##          3                                                  K                                                                                     ##STR50##          3                                                  (-)                                                                                   ##STR51##          4                                                  (-)                                                                                   ##STR52##          4                                                  (-)                                                                                   ##STR53##          3                                                  (-)                                                                                   ##STR54##          3                                                  (-)                                                                                   ##STR55##          4                                                  (-)                                                                                   ##STR56##          7                                                  (-)                                                                                   ##STR57##          7                                                  (-)                                                                                   ##STR58##          7                                                  (-)                                                                                   ##STR59##          4                                                  (-)                                                                                   ##STR60##          4                                                  (-)                                                                                   ##STR61##          4                                                  (-)                                                                                   ##STR62##          1                                                  (-)                                                                                   ##STR63##          7                                                  (-)                                                                                   ##STR64##          4                                                  (-)                                                                                   ##STR65##          7                                                  (-)                                                                                   ##STR66##          3                                                  (-)                                                                                   ##STR67##          3                                                  (-)                                                                                   ##STR68##          3                                                  (-)                                                                                   ##STR69##          3                                                  H                                                                                     ##STR70##          3                                                  (-)                                                                                   ##STR71##          3                                                  (-)                                                                                   ##STR72##          3                                                  (-)                                                                                   ##STR73##          3                                                  (-)                                                                                   ##STR74##          3                                                  (-)                                                                                   ##STR75##          2                                                  K                                                                                     ##STR76##          3                                                  K                                                                                     ##STR77##          3                                                  (-)                                                                                   ##STR78##          7                                                  (-)                                                                                   ##STR79##          3                                                  (-)                                                                                   ##STR80##          4                                                  (-)                                                                                   ##STR81##          4                                                  K                                                                                     ##STR82##          4                                                  K                                                                                     ##STR83##          3                                                  (-)                                                                                   ##STR84##          3                                                  (-)                                                                                   ##STR85##          7                                                  __________________________________________________________________________                 R.sup.a              R.sup.a                                     M   R.sup.a  Position                                                                           R.sup.a         Position                                    __________________________________________________________________________    (-) CN       7                                                                                   ##STR86##      3                                           (-) SOCH.sub.3                                                                             7                                                                                   ##STR87##      3                                           (-) CO.sub.2 K                                                                             7                                                                                   ##STR88##      3                                           (-) SO.sub.3 K                                                                             7                                                                                   ##STR89##      3                                           (-)                                                                                ##STR90##                                                                             7                                                                                   ##STR91##      4                                           (-) SO.sub.2 CH.sub.3                                                                      7                                                                                   ##STR92##      4                                           (-) CN       7                                                                                   ##STR93##      4                                           (-) CONH.sub.2                                                                             7                                                                                   ##STR94##      3                                           (-) CONH.sub.2                                                                             7                                                                                   ##STR95##      4                                           (-)                                                                                ##STR96##                                                                             7    CH.sub.2 CH.sub.2 CO.sub.2 Na                                                                 3                                           Na  CN       7                                                                                   ##STR97##      3                                           (-) SO.sub.3 K                                                                             3                                                                                   ##STR98##      4                                           (-) CHO      7                                                                                   ##STR99##      3                                           __________________________________________________________________________

The carbapenem compounds of the present invention are useful per se andin their pharmaceutically acceptable salt and ester forms in thetreatment of bacterial infections in animal and human subjects. The term"pharmaceutically acceptable ester or salt" refers to those salt andester forms of the compounds of the present invention which would beapparent to the pharmaceutical chemist, i.e., those which are non-toxicand which would favorably affect the pharmacokinetic properties of saidcompounds, their palatabilty, absorption, distribution, metabolism andexcretion. Other factors, more practical in nature, which are alsoimportant in the selection, are cost of the raw materials, ease ofcrystallization, yield, stability, hygroscopicity, and flowability ofthe resulting bulk drug. Conveniently, pharmaceutical compositions maybe prepared from the active ingredients in combination withpharmaceutically acceptable carriers. Thus, the present invention isalso concerned with pharmaceutical compositions and methods of treatingbacterial infections utilizing as an active ingredient the novelcarbapenem compounds of the present invention.

The pharmaceutically acceptable salts referred to above may take theform --COOM. The M may be an alkali metal cation such as sodium orpotassium. Other pharmaceutically acceptable cations for M may becalcium, magnesium, zinc, ammonium, or alkylammonium cations such astetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium,meglumine, triethanolhydroammonium, etc.

The pharmaceutically acceptable salts referred to above may also includenon-toxic aid addition salts. Thus, the Formula I compounds can be usedin the form of salts derived from inorganic or organic acids. Includedamong such salts are the following: acetate, adipate, alginate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate,camphorate, camphorsulfonate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalene-sulfonate, nicotinate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.

The pharmaceutically acceptable esters of the novel carbapenem compoundsof the present invention are such as would be readily apparent to amedicinal chemist, and include, for example, those described in detailin U.S. Pat. No. 4,309,438, Column 9, line 61 to Column 12, line 51,which is incorporated herein by reference. Included within suchpharmaceutically acceptable esters are those which are hydrolyzed underphysiological conditions, such as pivaloyloxymethyl, acetoxymethyl,phthalidyl, indanyl and methoxymethyl, and those described in detail inU.S. Pat. No. 4,479,947, which is incorporated herein by reference.

The novel carbapenem compounds of the present invention may take theform COOM, where M is a readily removable carboxyl protecting group.Such conventional blocking groups consist of known ester groups whichare used to protectively block the carboxyl group during the synthesisprocedures described above. These conventional blocking groups arereadily removable, i.e., they can be removed, if desired, by procedureswhich will not cause cleavage or other disruption of the remainingportions of the molecule. Such procedures include chemical and enzymatichydrolysis, treatment with chemical reducing or oxidizing agents undermild conditions, treatment with a transition metal catalyst and anucleophile, and catalytic hydrogenation. Broadly, such ester protectinggroups include alkyl, substituted alkyl, benzyl, substituted benezyl,aryl, substituted aryl, allyl, substituted allyl and triorganosilyl.Examples of specific such ester protecting groups include benzhydryl,p-nitrobenzyl, 2-naphthylmethyl, allyl, 2-chloroallyl, benzyl,2,2,2-trichloroethyl, trimethylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, 2-(trimethylsilyl)ethyl, phenacyl,p-methoxybenzyl, acetonyl, o-nitrobenzyl, 4-pyridylmethyl and t-butyl.

The compounds of the present invention are valuable antibacterial agentsactive against various Gram-positive and to a lesser extentGram-negative bacteria and accordingly fluid utility in human andveterinary medicine. The antibacterials of the invention are not limitedto utility as medicaments; they may be used in all manner of industry,for example: additives to animal feed, preservation of food,disinfectants, and in other industrial systems where control ofbacterial growth is desired. For example, they may be employed inaqueous compositions in concentrations ranging from 0.1 to 100 parts ofantibiotic per million parts of solution in order to destroy or inhibitthe growth of harmful bacteria on medical and dental equipment and asbactericides in industrial applications, for example in waterbasedpaints and in the white water of paper mills to inhibit the growth ofharmful bacteria.

The compounds of this invention may be used in any of a variety ofpharmaceutical preparations. They may be employed in capsule, powderform, in liquid solution, or in suspension. They may be administered bya variety of means; those of principal interest include: topically orparenterally by injection (intravenously or intramuscularly).

Compositions for injection, a preferred route of delivery, may beprepared in unit dosage form in ampules, or in multidose containers. Thecompositions may take such forms as suspensions, solutions, or emulsionsin oily or aqueous vehicles, and may contain formulatory agents.Alternatively, the active ingredient may be in powder form forreconstitution, at the time of delivery, with a suitable vehicle, suchas sterile water. Topical applications may be formulated in hydrophobicor hydrophilic bases as ointments, creams, lotions, paints, or powders.

The dosage to be administered depends on a large extent upon thecondition and size of the subject being treated as well as the route andfrequency of administration, the parenteral route by injection beingpreferred for generalized infections. Such matters, however, are left tothe routine discretion of the therapist according to principles oftreatment well known in the anti-bacterial art. Another factorinfluencing the precise dosage regimen, apart from the nature of theinfection and peculiar identity of the individual being treated, is themolecular weight of the chosen species of this invention.

The compositions for human delivery per unit dosage, whether liquid orsolid, may contain from 0.1% to 99% of active material, the preferredrange being from about 10-60%. The composition will generally containfrom about 15 mg to about 1500 mg of the active ingredient; however, ingeneral, it is preferable to employ a dosage amount in the range of fromabout 250 mg to 1000 mg. In parenteral administration, the unit dosageis usually the pure compound I in sterile water solution or in the formof a soluble powder intended for solution.

The preferred method of administration of the Formula I antibacterialcompounds is parenteral by i.v. function, i.v. bolus, or i.m. injection.

For adults, 5-50 mg of Formula I antibacterial compounds per kg of bodyweight given 2, 3 or 4 times per day is preferred. Preferred dosage is250 mg to 1000 mg of the Formula I antibacterial given two (b.i.d.)three (t.i.d.) or four (q.i.d.) times per day. More specifically, formild infections a dose of 250 mg t.i.d. or q.i.d. is recommended. Formoderate infections against highly susceptible gram positive organisms adose of 500 mg t.i.d. or q.i.d. is recommended. For severe,life-threatening infections against organisms at the upper limits ofsensitivity to the antibiotic, a dose of 1000 mg t.i.d. or q.i.d. isrecommended.

For children, a dose of 5-25 mg/kg of body weight give 2, 3 or 4 timesper day is preferred; a dose of 10 mg/kg t.i.d. or q.i.d. is usuallyrecommended.

Antibacterial compounds of Formula I are of the broad class known ascarbapenems or 1-carbadethiapenems. Naturally occuring carbapenems aresusceptible to attack by a renal enzyme known as dehydropeptidase (DHP).This attack of degradation may reduce the efficacy of the carbapenemantibacterial agent. The compounds of the present invention, on theother hand, are significantly less subject to such attack, and thereforemay not require the use of DHP inhibitor. However, such use is optionaland contemplated to be part of the present invention. Inhibitors of DHPand their use with carbapenem antibacterial agents are disclosed in theprior art [see European Patent Applications No. 79102616.4 filed Jul.24, 1979 (Patent No. 0 007 614); and No. 82107174.3, filed Aug. 9, 1982(Publication No. 0. 072 014)].

The compounds of the present invention may, where DHP inhibition isdesired or necessary, be combined or used with the appropriate DHPinhibitor as described in the aforesaid patents and publishedapplication. Thus, to the extent that the cited European patentapplications 1.) define the procedure for determining DHP susceptibilityof the present carbapenems and 2.) disclose suitable inhibitors,combination compositions and methods of treatment, they are incorporatedherein by reference. A preferred weight ratio of Formula I compound: DHPinhibitor in the combination compositions is about 1:1. A preferred DHPinhibitor is7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoicacid or a useful salt thereof.

The benzocoumarin rings of formula I is not numbered in this text andclaims as convention dictates. In the examples, conventional numberingof these rings is employed per the formula: ##STR100##

EXAMPLE 1 ##STR101##

Chlorotrimethylsilane (10.4 mL, 81.9 mmol, 3.0 eq) was added to astirred solution of 1 (7.0 g, 27.3 mmol) in dry THF (103 mL) at -78° C.under N₂. Tert-butyllithium (23.1 mL, 30 mmol, 1.1 eq) was addeddropwise at -78° C. over 45 minutes. The reaction mixture was warmed to0° C. with an ice bath and then quenched with saturated ammoniumchloride solution (25 mL). After removal of THF in vacuo the reactionmixture was poured into ether (400 mL) and washed with water, saturatedsodium bicarbonate solution (2×50 mL), water, and brine. The etherallayer was dried (MgSO₄), filtered, and evaporated in vacuo. Purificationusing flash chromatography (20% EtOAc/hex) afforded 5.7 g (87%) of arylsilane 2, a white solid.

¹ H-NMR for 2 [400 MHz, CDCl₃, rotamers]: δ 0.24 (s, 9H), 1.08 (broad s,3H), 1.21 (broad s, 3H), 3.23 (broad s, 2H), 3.51 (broad s, 2H), 7.30(d, J=8.1 Hz, 2H), 7.50 (d, J=8.1 Hz, 2H).

IR(CHCl₃): 3010, 1615 cm⁻¹.

EXAMPLE 2 ##STR102##

To a stirred solution of N,N,N',N'-tetramethylethylenediamine (2.7 mL,17.6 mmol, 1.1 eq) in anhydrous THF (100 mL) at -78° C. under N₂ wasadded dropwise sec-butyllithium (13.0 mL, 16.8 mmol, 1.05 eq). After 15minutes the yellow mixture was treated with a solution of 2 (4.0 g, 16.0mmol) in dry THF (40 mL), and the resultant red mixture was stirred for1 hour at -78° C. Trimethylborate (2.0 mL, 17.6 mmol, 1.1 eq) was addeddropwise. The reaction flask was warmed to 0° C. with an ice bath andthen stirred for 5 minutes. The green reaction mixture was quenched with8% HCl solution (60 mL), stirred for 10 minutes, and the organic solventconcentrated in vacuo. The mixture was poured into ether and theethereal layer was washed with water (2×), brine, dried (MgSO₄),filtered, and evaporated in vacuo. Purification using flashchromatography (5:3:1 EtOAc/acetone/H₂ O) provided 3.77 g (80%) ofboronic acid 3, a white foam.

¹ H-NMR for 3 [200 MHz, CDCl₃, rotamers]: δ 0.27 (s, 9H), 0.88 to 1.16(m, 6H), 3.27 to 3.36 (m, 4H), 7.28 (d, J=6.4 Hz, 1H), 7.52 (d, J=7.6Hz, 1H), 8.15 (s, 1H). IR(CHCl₃): 2960, 1615, 1601 cm⁻¹.

EXAMPLE 3 ##STR103##

To a solution of bromo-hydroxybenzoic acid (1.0 g, 4.6 mmol) in dry THF(30 mL) cooled to 0° C. under N₂ was added THF.BH₃ (13.8 mL, 13.8 mmol,3.0 eq) dropwise. Upon completion of addition, the ice bath was removedand the solution heated to reflux for 30 minutes. The reaction vesselwas cooled to 0° C. and quenched by dropwise addition of MeOH (30 mL)containing triethylamine (1 mL). The solvents were then removed invacuo. The residual was dissolved in MeOH and the MeOH removed in vacuo(3×). The remaining solid was dissolved in pyridine (10 mL) and treatedwith acetic anhydride (10 mL). After being stirred at ambienttemperature for one hour the contents of the reaction vessel were pouredinto Et₂ O and washed with 2N HCl solution (2×), H₂ O (1×), 2N HCl (2×),and brine. The etheral layer was dried (MgSO₄), filtered and evaporatedin vacuo. The residual oil was passed through a short plug of SiO₂ usingEtOAc/hex (20%) as an eluent to provide 1.32 g (quantitative yield) ofbis-acetate 4.

¹ H-NMR (400 MHz, CDCl₃) δ 2.09 (s, 3H), 2.34 (s, 3H), 5.04 (s, 2H),7.08-7.14 (m, 2H), 7.57 (d, J=8.0 Hz, 1H).

EXAMPLE 4 ##STR104##

To boronic acid 3 (200.0 mg; 0.68 mmol) in toluene (5.0 mL) was addedtetrakis(triphenylphosphine)palladium(0) (23.0 mg; 3 mol %), Na₂ CO₃(680 μL; 1.36 mmol; 2.0 eq) and arylbromide 5 (196.0 mg; 0.68 mmol; 1.0eq) in ethanol (2.0 mL). The heterogeneous mixture was heated to refluxfor 60 minutes under an atmosphere of nitrogen. The reaction mixture wasthen poured into Et₂ O and washed with H₂ O (3×), brine (2×), dried(MgSO₄), filtered and the solvent removed in vacuo. Purification byflash chromatography (40% EtOAc/hex) provided 147.0 mg (47%) of biphenyl5.

¹ H-NMR (400 MHz, CDCl₃, Rotamers) δ 0.24 (s, 9H), 0.75 (t, J=6.5 Hz,3H), 0.85 (t, J=6.5 Hz, 3H), 2.04 (s, 3H), 2.08 (s, 3H), 2.60-3.10(broad, 3H), 3.55-3.85 (b, 1H), 5.08 (s, 2H), 7.13 (s, 1H, ), 7.20 (d,J=8.0 Hz, 1H), 7.33 (d, J=6.4 Hz, 1H), 7.39 (s, 1H), 7.41-7.48 (broad,1H), 7.52 (d, J=6.4 Hz, 1H).

EXAMPLE 5 ##STR105##

To a solution of biphenyl 5 (98.0 mg; 0.215 mmol) in dichloromethane (1mL) at ambient temperature was added ICl (2.15 mL; 2.15 mmol; 10.0 eq)in dichloromethane dropwise slowly. The reaction mixture was stirredovernight. The following morning, the reaction mixture was poured intoEt₂ O, washed with saturated sodium thiosulfate solution, H₂ O, andbrine. The etheral layer was dried (MgSO₄), filtered and solvent removedin vacuo to afford 110 mg (quantitative yield) of iodide 6. ¹ H-NMR (200MHz, CDCl₃, Rotamers) δ 0.70-0.91 (m, 6H), 2.10 (s, 3H), 2.15 (s, 3H),2.60-3.10 (broad, 3H), 3.30-3.80 (broad, 1H), 5.10 (s, 2H), 7.10-7.29(complex m, 3H), 7.42 (d, J=7.2 Hz, 1H), 7.67 (s, 1H), 7.78 (d, J=7.6Hz, 1H).

EXAMPLE 6 ##STR106##

To a stirred solution of iodide 6 (109.0 mg, 0.215 mmol) in MeOH (8 mL)was added a 25% weight solution of NaOMe (250 μL, 1.15 mmol, 5.3 eq).Upon consumption of 6 as indicated by SiO₂ TLC (50% EtOAc/hex), thereaction mixture was poured into Et₂ O and washed sequentially withsaturated NH₄ Cl solution, H₂ O, and brine. After drying (MgSO₄),filtration and removal of the solvent in vacuo, the crude residue wassuspended in toluene (10 mL) and heated to reflux in the presence of acatalytic amount of p-toluenesulfonic acid. Upon consumption of theintermediate diol as indicated by SiO₂ TLC (50% EtOAc/hex), the reactionmixture was poured into Et₂ O and washed sequentially with saturatedNaHCO₃ solution, H₂ O and brine. Drying (MgSO₄), filtration and removalof the solvent in vacuo provided 75.7 mg (quantitative yield) of thebenzocoumarin 7, a white solid.

¹ H-NMR (400 MHz, D₆ DMSO) δ 4.18 (s, 2H), 6.88 (m, 2H), 7.53 (m, 2H),7.85 (m, 1H), 8.35 (s, 1H).

EXAMPLE 7 ##STR107##

To iodide 7 (510.0 gm, 1.45 mmol) in toluene (25 mL) was addedtetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0725 mmol, 5 mol%), triphenylphosphine (11.0 mg, 0.044 mmol, 3 mol %) andhexamethylditin (327.6 mg, 1.59 mmol, 1.1 eq). Nitrogen was then bubbledthrough the solution for approximately 5 minutes before the mixture washeated to reflux under nitrogen. Upon consumption of iodide 7 asindicated by SiO₂ TLC (50% EtOAc/hex), the reaction mixture was pouredinto EtOAc and washed with saturated NaHCO₃ (2×) (1×) and brine (1×).The organic layer was dried (MgSO₄), filtered and evaporated in vacuo toprovide a tan solid which was repeatedly precipitated from EtOAc/hex toprovide 458 mg (81%) of stannane 8, a tan solid.

¹ H-NMR (400 MHz, D₆ Acetone) δ 0.41 (s, 9H), 4.75 (s, 2H), 7.36-7.39(m, 2H), 7.82 (d, J=7.6 Hz, 1H), 8.22 (d, J=7.6 Hz, 1H), 8.34 (d, J=8.0Hz, 1H), 8.55 (s, 1H).

EXAMPLE 8 ##STR108##

To a stirred solution of the bicyclic β-keto ester 9 (134.6 mg, 0.386mmol) in dry THF (2.0 mL) at -78° C. under N₂ was added diisopropylamine(60.0 μL, 0.43 mmol, 1.1 eq). The resultant yellow mixture was stirredfor 10 minutes before trifluoromethanesulfonic anhydride (71.0 μL, 0.43mmol, 1.1 eq) was added. After 15 minutes triethylamine (60.0 μL, 0.43mmol, 1.1 eq), followed by the trimethylsilyl trifluoromethanesulfonate(82.0 μL, 0.43 mmol, 1.1 eq), was added and the reaction mixture wasstirred for 20 minutes.

The reaction mixture was then treated sequentially with anhydrousN-methylpyrrolidinone (2.0 mL), the Pd₂ (dba)₃.CHCl₃ catalyst (8.0 mg,2.0 mol %), the aryl stannane 8 (100.0 gm, 0.257 mmol, 0.66 eq), andzinc chloride (0.19 mL, 0.257 mmol, 0.66 eq). The low temperature bathwas then removed and the reaction vessel was placed in a warm water bathto quickly reach ambient temperature. The solution was stirred for 15minutes at ambient temperature.

The reaction was then poured into ether and washed with saturated sodiumbicarbonate solution, water and brine. The organic layer was dried(MgSO₄), filtered and evaporated in vacuo. Purification using flashchromatography (65% EtOAc/hex) provided 146 mg (90%) of the coupledproduct 10.

¹ H-NMR (400 MHz, CDCl₃) δ 0.14 (s, 9H), 1.29 (d, J=6.2 Hz, 3H), 2.34(t, J=6.0 Hz, 1H), 3.25-3.34 (complex m, 2H), 3.41 (1/2 ABX, J_(AB)=18.5 Hz, J_(AX) =8.9 Hz, 1H), 4.23-4.29 (m, 1H), 4.34 (dt, J=10.0, 3.0Hz, 1H), 4.74 (d, J=5.8 Hz, 2H), 5.22 (ABq, J_(AB) =13.5 Hz, Δυ_(AB)=69.8 Hz, 2H), 7.23 (d, J=8.0 Hz, 1H), 7.28 (s, 1H), 7.40 (d, J=8.8 Hz,2H), 7.44 (dd, J=8.3, 1.6 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.95 (d,J=1.5 Hz, 1H), 7.99 (d, J=8.7 Hz, 2H), 8.27 (d, J=8.3 Hz, 1H).

I.R. (CHCl₃), 3640-3580, 3020, 2960, 1780, 1730, 1610, 1540 cm⁻¹.

U.V. (CH₃ CN) λ=322 nm; ε=13,500; λ=305 mn; ε=16,900.

EXAMPLE 9 ##STR109##

To a stirred solution of 10 (66.0 mg, 0.105 mmol) in THF/H₂ O (9 mL,2:1) cooled to 0° C. was added HCl in Et₂ O (52.0 μL, 0.052 mmol, 0.5eq). After ten minutes at 0° C., a solution of NaHCO₃ (210 μL, 0.21mmol, 2.0 eq) was added followed by 10% Pd/C (6.6 mg, 10 wt. %). The icebath was removed and the reaction vessel placed under an atmosphere ofH₂ employing a balloon. After 45 minutes, the H₂ atmosphere was replacedby N₂ and the stirring was continued for an additional 15 minutes. Thereaction mixture was then filtered through a pad of Celite using H₂ O asthe eluent. The THF was removed in vacuo and the remaining H₂ Olyophilized at 0° C. The resulting solid was purified using reversephase prep-plate chromatography (6:1 H.sub. 2 O/CH₃ CN) to afford 35.7mg (76.6%) of carbapenem 11.

¹ H-NMR (400 MHz, D₂ O/CD₃ CN 2:1) δ 1.61 (d, J=6.5 Hz, 3H), 3.50 (1/2ABX, J_(AB) =16.5 Hz, J_(AX) =9.8 Hz, 1H), 3.81-3.88 (complex m, 2H),4.51-4.57 (m, 1H), 4.65 (dt, J=9.7, 3.2 Hz, 1H), 5.02 (s, 3H), 7.67 (s,1H), 7.71 (d, J=8.3 Hz, 1H), 7.92 (d, J=8.3 Hz, 1H), 8.46 (d, J=8.2 Hz,1H), 8.48-8.51 (m, 2H).

I.R. (KBr) 1755, 1715, 1610 cm⁻¹.

U.V. (MOPS BUFFER) λ=330 nm, ε=14,700; λ_(ext) =340 nm, ε_(ext) =10,500.

EXAMPLE 10 ##STR110##

A stirred solution of 10 (33.0 mg, 0.0526 mmol),N-methylmorpholine-N-oxide (9.2 mg, 0.0788 mmol, 1.5 eq), and powdered 4Å molecular sieves (26.0 mg, 500 mg/mmol) in dry dichloromethane (1.0mL) was treated with tetrapropylammonium perruthenate (1.0 mg, 5.0 mol%) at room temperature under N₂. After 20 minutes, an additional 0.5 mgof "TPAP" was added to drive the reaction to completion. The reactionmixture was stirred for an additional 5 minutes before the resultingblack mixture was filtered through a short-column of silica gel using70% EtOAc/hex as an eluant. The filtrate was evaporated in vacuo toafford 21.0 mg (64%) of aldehyde 12.

¹ H-NMR (400 MHz, CDCl₃) δ 0.14 (s, 9H), 1.29 (d, J=6.3 Hz, 3H),3.27-3.36 (complex m, 2H), 3.43 (1/2 ABX, J_(AB) =18.3 Hz, J_(AX) =8.7Hz, 1H), 4.24-4.30 (m, 1H), 4.37 (dt, J=10.0, 2.8 Hz, 1H), 5.28 (ABq,J_(AB) =14.2 Hz, Δυ_(AB) =68.1 Hz, 2H), 7.50 (d, J=8.6 Hz, 2H), 7.58(dd, J=8.3, 1.5 Hz, 1H), 7.80-7.83 (m, 2H), 8.04-8.11 (m, 3H), 8.18 (s,1H), 8.37 (d, J=8.4 Hz, 1H), 10.05 (s, 1H).

I.R. (CHCl₃) 3030, 2970, 1785, 1740, 1705, 1610, 1525.

U.V. (CH₃ CN) λ=320 nm, ε=20,400; λ=291 n, ε=26,500.

EXAMPLE 11 ##STR111##

From 12 (21.0 mg, 0.0340 mmol) employing the general deprotectionprocedure as described for compound 10, was provided 4.6 mg (30%) ofcarbapenem 13.

¹ H NMR (400 MHz, 2:1 D₂ O/CD₃ CN) δ 1.64 (d, J=6.3 Hz, 3H), 3.54 (1/2ABX, J_(AB) =16.5 Hz, J_(AX) =9.9 Hz, 1H), 3.85-3.92 (complex m, 2H),4.53-4.60 (m, 1H), 4.66-4.72 (m, 1H), 8.07 (d, J=8.1 Hz, 1H), 8.23 (d,J=1.4 Hz, 1H), 8.29 (d, J=8.1 Hz, 1H), 8.59 (d, J=8.4 Hz, 1H), 8.64 (s,1H), 8.74 (d, J=8.1 Hz, 1H), 10.37 (s, 1H).

I.R. (KBr) 1730, 1695, 1610 cm⁻¹.

U.V. (MOPS BUFFER) λ=302 nm, ε=18,000; λ_(ext) =315 nm, ε_(ext) =8,500.

EXAMPLE 12 ##STR112##

To a stirred solution of alcohol 8 (100.0 mg, 0.257 mmol) dissolved inanhydrous pyridine (1.0 mL) was added a solution of ^(n) Bu₄ NMO₄ (123.0mg, 0.342 mmol, 1.33 eq) in anhydrous pyridine (1.0 mL) dropwise. After15 minutes the reaction mixture was poured into Et₂ O and washedsequentially with NaHSO₃ solution, 1N HCl solution, water and brine. Theethereal layer was dried (MgSO₄), filtered and evaporated in vacuo toprovide the crude acid which was not isolated but instead dissolved inTHF (6.5 mL) and CH₃ CN (1.5 mL) and sequentially treated with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (98.5 mg,0.514 mmol, 2 eq), 1-hydroxybenzotriazole hydrate (104.2 mg, 0.771 mmol,3 eq) and ethanolic ammonia (500 μL, 1.28 mmol, 5 eq). The resultingmilky white solution was stirred for approximately 1 hour before beingquenched with saturated ammonium chloride. After removal of the THF andCH₃ CN in vacuo, the residual was poured into Et₂ O and washed with H₂ Oand brine. The ethereal layer was dried (MgSO₄), filtered and evaporatedin vacuo. Recrystallization provided 25.0 mg of pure 14. Flashchromatography of the mother liquor (100% EtOAc/hex) provided another22.0 mg of 14 totaling 45% yield.

¹ H NMR (200 MHz, CDCl₃) δ 0.43 (s, 9H), 5.70-6.30 (broad, 2H),7.75-7.90 (complex m, 3H), 8.20 (d, J=8.3 Hz, 1H), 8.27 (s, 1H), 8.32(d, J=7.7 Hz, 1H).

I.R. (CHCl₃) 3520, 3420, 3020, 2920, 1730, 1680, 1600 cm⁻¹.

EXAMPLE 13 ##STR113##

Compound 15 (50.6 mg, 70% yield) was obtained according to the generalcoupling procedure described for the manufacture of compound 10, exceptthat stannane 14 was employed rather than stannane 8.

¹ H NMR (300 MHz, CDCl₃) δ 0.14 (s, 9H, 1.30 (d, J=6.2 Hz, 3H),3.25-3.37 (complex m, 2H), 3.45 (1/2 ABX, J_(AB) =18.5, J_(AX) =8.9 Hz,1H), 4.23-4.32 (m, 1H), 4.37 (dt, J=9.9, 2.8 Hz, 1H), 5.25 (ABq, J_(AB)=13.6 Hz, Δυ_(AB) =49.8 Hz, 2H), 5.85-6.10 (broad, 1H), 6.35-6.60(broad, 1H), 7.45 (d, J=8.8 Hz, 2H), 7.52 (dd, J=8.2, 1.5 Hz,1H),7.71-7.74 (m, 2H), 7.89 (d, J=8.2 Hz, 1H), 8.03-8.07 (m, 3H), 8.29(d, J=8.2 Hz, 1H).

I.R. (CHCl₃) 3520, 3420, 3020, 2960, 1780, 1730, 1680, 1610 cm⁻¹.

U.V. (CH₃ CN) λ=310 nm, ε=400.

EXAMPLE 14 ##STR114##

From 15 (25.0 mg, 0.039 mmol) employing the general deprotectionprocedure as described for compound 10, was provided 12.5 mg (70%) ofcarbapenem 16.

¹ H-NMR (400 MHz, 2:1 D₂ O/CD₃ CN) δ 1.62 (d, J=6.5 Hz, 3H), 3.52 (1/2ABX, J_(AB) =15.7 Hz, J_(AX) =9.1 Hz, 1H), 3.83-3.90 (complex m, 2H),4.54-4.58 (m, 1H), 4.67 (t, J=8.0 Hz, 1H), 8.01 (d, J=8.2 Hz, 1H), 8.13(s, 1H), 8.16 (d, J=8.4 Hz, 1H), 8.54-8.58 (m, 2H), 8.61 (d, J=8.4 Hz,1H).

I.R. (KBr) 1725, 1670, 1600.

U.V. (MOPS BUFFER) λ=308 nm, ε=15,000; λ_(ext) =342 nm, ε_(ext) =9,400.

EXAMPLE 15 ##STR115##

To o-bromophenol (500 mg, 2.89 mmol) in pyridine (5 mL) was added aceticanhydride (5 mL). Upon consumption of the starting material by SiO₂ TLC,the solvents were removed in vacuo to provide 621.0 mg (quantitativeyield) of aryl bromide 17.

¹ H-NMR (200 MHz, CDCl₃) δ 2.35 (s, 3H), 7.08-7.18 (m, 2H), 7.25-7.40(m, 1H), 7.58-7.65 (m, 1H).

EXAMPLE 16 ##STR116##

From 3 (70.0 mg, 0.24 mmol) and 17 (51.0 mg, 0.24 mmol) following theSuzuki procedure as described for the manufacture of compound 5 wasprovided 44.0 mg (48%) of biphenyl 18.

¹ H-NMR (200 MHz, CDCl₃, Rotamers) δ 0.28 (s, 9H), 0.72-0.80 (complex m,6H), 2.09 (s, 3H), 2.60-3.90 (broad, 4H), 7.13-7.60 (complex m, 7H).

I.R. (CHCl₃) 3000, 2860, 2800, 1760, 1740, 1610 cm⁻¹.

EXAMPLE 17 ##STR117##

To a stirred solution of biphenyl 18 (161 mg, 0.42 mmol) in MeOH (5 mL)was added a 25% weight solution of NeOMe (9.0 μL, 0.042 mmol, 10 mol %).After approximately one hour, toluene was added (15 mL) followed byTsOH.H₂ O (16.0 mg, 0.084 mmol, 20 mol %). The reaction mixture was thenheated to reflux under a Dean-Stark apparatus for 20 minutes. Thereaction mixture was then poured into Et₂ O and washed with saturatedsodium bicarbonate solution (3×) and brine (2×), dried (MgSO₄), filteredand the solvent removed in vacuo. Purification by flash chromatography(15% EtOAc/hex) provided 71.5 mg (63%) of benzocoumarin 19, a whitecrystalline solid.

¹ H-NMR (200 MHz, CDCl₃) δ 0.39 (s, 9H), 7.31-7.52 (complex m, 3H), 7.73(d, J=8.7 Hz, 1H), 8.14 (d, J=8.0 Hz, 1H), 8.27 (s, 1H), 8.35 (d, J=7.7Hz, 1H).

I.R. (CHCl₃) 3010, 2980, 1728, 1600.

EXAMPLE 18 ##STR118##

To a solution of 19 (71.5 mg, 0.266 mmol) in CH₂ Cl₂ (1 mL) was added asolution of IC1 (1.33 mL, 1.33 mmol, 5.0 eq) in CH₂ Cl₂ over a period ofone hour. Upon completion of addition, the reaction mixture was pouredinto Et₂ O and washed with aqueous Na₂ S₂ O₄ solution, H₂ O and brine.The ethereal layer was dried over MgSO₄, filtered and the solventremoval in vacuo to provide 85.6 mg (quantitative yield) of iodide 20.

¹ H-NMR (200 MHz, CDCl₃) δ 7.32-7.40 (m, 2H), 7.48-7.56 (m, 1H), 7.92(d, J=8.5 Hz, 1H), 8.05 (d, J=8.2 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H), 8.50(s, 1H).

I.R. (CHCl₃) 3010, 1730, 1600 cm⁻¹.

EXAMPLE 19 ##STR119##

Iodide 20 (87.0 mg, 0.266 mmol) was dissolved in dry toluene (10 mL).Tetrakis(triphenylphosphine) palladium(O) (15 mg, 5 mol %) was addedfollowed by triphenylphosphine (2 mg, 3 mol %) and hexamethylditin (96.0mg, 0.29 mmol, 1.1 eq). Nitrogen was then bubbled through the solutionfor 5 minutes before the mixture was heated to reflux under nitrogen.Upon reaction completion (TLC), the mixture was poured into Et₂ O andwashed with saturated NaHCO₃ solution, H₂ O and brine. The etheral layerwas dried (MgSO₄), filtered and solvent remove in vacuo. Purification byflash chromatography (5% EtOAc/hex) provided 71 mg (74%) of stannane 21.

¹ H-NMR (200 MHz, CDCl₃) δ 0.42 (s, 9H), 7.31-7.53 (complex m, 3H), 7.73(d, J=7.8 Hz, 1H), 8.13 (d, J=7.8 Hz, 1H), 8.26 (s, 1H), 8.32 (d, J=7.8Hz, 1H).

I.R. (CHCl₃) 3020, 2980, 2920, 1725, 1600 cm⁻¹.

EXAMPLE 20 ##STR120##

From 9 (103.0 mg, 0.30 mmol) and stannane 21 (71.0 mg, 0.2 mmol, 0.66eq) following the general cross-coupling procedure as described forcompound 10 was obtained 82.0 mg (69%) of 22.

¹ H-NMR (400 MHz, CDCl₃) δ 0.14 (s, 9H), 1.30 (d, J=6.1 Hz, 3H),3.26-3.33 (complex m, 2H), 3.41 (1/2 ABX, J_(AB) =18.3 Hz, J_(AX) =8.8Hz, 1H), 4.25-4.28 (m, 1H), 4.33-4.38 (dt, J=9.8, 2.8 Hz, 1H), 5.24(ABq, J_(AB) =13.5 Hz, Δυ_(AB) =64.0 Hz, 2H), 7.26-7.35 (m, 2H),7.43-7.87 (m, 3H), 7.87 (d, J=6.6 Hz, 1H), 8.04-8.07 (m, 2H), 8.33 (d,J=8.4 Hz, 1H).

I.R. (CHCl₃) 3020, 2960, 1760, 1730, 1610, 1520, cm⁻¹.

EXAMPLE 21 ##STR121##

From 22 (41.0 mg, 0.068 mmol) following the general descriptionprocedure as described for compound 11 was obtained 4.4 mg (15%) ofcarbapenem 23.

¹ H-NMR (400 MHz, 2:1 D₂ O/CDCl₃) δ 1.60 (d, J=6.3 Hz, 3H), 3.51 (1/2ABX, J_(AB) =16.8 Hz, J_(AX) =10.0 Hz, 1H), 3.81-3.90 (complex m, 2H),4.52-4.56 (m, 1H), 4.65 (t, J=8.0 Hz, 1H), 7.74 (d, J=8.1 Hz, 1H),7.78-7.80 (m, 2H), 7.89-7.98 (m, 2H), 8.54-8.56 (m, 3H).

I.R. (KBr) 1780-1720 (broad), 1610 cm⁻¹

U.V. (MOPS BUFFER) λ=328 nm, ε=10,500; λ_(ext) =338 nm, ε_(ext) =7,100.

EXAMPLE 22 ##STR122##

Compound 10 (146.0 mg, 0.23 mmol) was dissolved in CH₂ Cl₂ (3.0 mL) andcooled to -78° C. under N₂. To this stirred solution was addedN-methylimidazole (46.0 μL, 0.58 mmol, 2.5 eq) followed bytrifluoromethanesulfonic anhydride (43.0 μL, 0.26 mmol, 1.1 eq). Thereaction vessel was then warmed to -30° to -20° C. for approximately tenminutes before being poured into EtOAc containing some Et₂ O. Theorganic layer was washed with H₂ O (5×), dried (Na₂ SO₄), filtered andevaporated in vacuo to provide 175.0 mg (89%) of compound 24 as a yellowfoam.

¹ H-NMR (400 MHz, CDCl₃) δ 0.14 (s, 9H), 1.30 (d, J=6.2 Hz, 3H), 3.29(1/2 ABX, J_(AB) =18.3 Hz, J_(AX) =10.1 Hz, 1H), 3.37 (dd, J=5.8, 2.8Hz, 1H), 3.45 (1/2 ABX, J_(AB) =18.6 Hz, J_(AX) =8.9 Hz, 1H), 4.00 (s,3H), 4.23-4.31 (m, 1H), 4.37 (dt, J=10.3, 2.9 Hz, 1H), 5.21 (ABq, J_(AB)=13.4 Hz, Δυ_(AB) =69.0 Hz, 2H), 5.47 (s, 3H), 7.20 (s, 1H), 7.27-7.46(complex m, 7H), 7.78 (d, J=8.4 Hz, 1H), 7.92-7.95 (m, 2H), 8.17 (d,J=8.1 Hz, 1H), 9.39 (s, 1H).

EXAMPLE 23 ##STR123##

Compound 25 (8.5 mg, 33%), was obtained from compound 24 (44.0 mg, 0.05mmol) employing the general deprotection procedure as described forcompound 10 except that 2.0 equivalents of HCl in Et₂ O at 0° C. for 1hour were used to remove the silyl group and 3.0 equivalents of NaHCO₃were used to neutralize the acid.

¹ H-NMR (400 MHz, 2:1, D₂ O/CDCl₃) 1.62 (d, J=6.1 Hz, 3H), 3.51 (1/2ABX, J_(AB) =15.3 Hz, J_(AX) =9.7 Hz, 1H), 3.82-3.90 (complex m, 2H),4.19 (s, 3H), 4.53-4.58 (m, 1H), 4.67 (dt, J=8.9, 2.4 Hz, 1H), 5.80 (s,2H), 7.73 (s, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H),8.54-8.60 (complex m, 4H).

I.R. (KBr) 1760, 1725, 1600 cm⁻¹

U.V. (MOPS BUFFER) λ=328 nm, ε=10,200; λ_(ext) =340 nm, ε_(ext) =7,600.

EXAMPLE 24 ##STR124##

To a stirred solution of 10 (33.0 mg, 0.053 mmol) in CH₂ Cl₂ (1.0 mL)cooled to -78° C. under N₂ was added collidine (8.3 μL, 0.063 mmol, 1.2equiv.) followed by trifluoromethanesulfonic anhydride (9.7 μL, 0.058mmol, 1.1 equiv.). After 35 minutes 4-methyl-1,2,4-triazole (9.6 mg,0.116 mmol, 2.2 equiv.) was added. The reaction vessel was warmed to-30° C. and stirred for 30 minutes before being poured into EtOAccontaining some Et₂ O. The organic layer was washed with H₂ O (4×),dried (Na₂ SO₄), filter and evaporator in vacuo. The residual solid wasdissolved in CH₂ Cl₂ and precipitated using Et₂ O (2×) to afford 26 mg(63%) of compound 26, a yellowish solid.

¹ H NMR (400 MHz, CDCl₃) δ 0.13 (s, 9H), 1.28 (d, J=6.2 Hz, 3 H), 3.26(1/2 ABX, J_(AB) =18.6 Hz, J_(AX) =10.2 Hz, 1H), 3.38 (dd, J=6.1, 3.0Hz, 1H), 3.45 (1/2 ABX, J_(AB) =18.3 Hz, J_(AX) =9.9 Hz, 1H), 4.17 (s,3H), 4.26 (m, 1H), 4.36 (t, J=9.8 Hz, 1H), 5.18 (ABq, J_(AB) =13.2 Hz,Δυ_(AB) =65.3 Hz, 2 H), 5.61 (s, 2 H), 7.33-7.44 (complex m, 6H), 7.75(d, J=8.4 Hz, 1H), 7.86(s, 1H), 7.89 (d, J=8.8 Hz, 2 H), 8.06 (d, J=8.4Hz, 1H), 8.74 (s, 1H).

IR(CHCl₃) 1775, 1725, 1601 cm⁻¹

U.V.(CH₃ CN) λ=305 nm, ε=19,500

EXAMPLE 25 ##STR125##

To a stirred solution of 26 (28 mg, 0.033 mmol) in 3 mL of THF/H₂ O(2:1)cooled to 0° C. was added 1M HCl solution (16.6 μL, 0.016 mmol, 0.5equiv.). After 16 minutes at 0° C., a 1M solution of NaHCO₃ (50.0 μL,0.05 mmol 1.5 equiv.) was added followed by 10% Pd/C (8.4 mg, 30% wt.).The ice bath was removed and the vessel placed under an atmospheric ofH₂ (balloon) for 1 hour. The reaction mixture was then filtered throughcelite using H₂ O as a eluent. Lyophilization of the H₂ O provided thecrude solid which was purified by reverse-phase prep-platechromatography (3:1 H₂ O/CH₃ CN) providing 11.9 mg (74%) of compound 27.

¹ H NMR(200 MHz, 2:1 D₂ O, CD₃ CN) δ 1.68 (d, J=6.4 Hz, 3H),3.50-3.68(m, 1H), 3.82-3.99 (m, 2H), 4.47 (s, 3H), 4.55-4.78 (m, 2H),5.97 (s, 3H), 7.82-7.92 (m, 2H), 8.05 (d, J=8.7 Hz, 1H), 8.59-8.68 (m,3H).

I.R. (KBr) 1755, 1730, 1610 cm⁻¹

U.V. (MOPS BUFFER) λ=330 nm, ε=12,000 λ_(ext) =340 nm, ε_(ext) =9,000

What is claimed is:
 1. A compound of the formula: ##STR126## wherein: Ris H or CH₃ ;X^(h) is O or S; P' is a removable protecting group forhydroxy; R^(a) are independently selected from the group consisting ofhydrogen and the radicals set out below, provided that one but not morethan one R^(a) is a Type I substituent, the remaining non-hydrogensubstituents being selected from Type II, and in total not more thanfour R^(a) radicals are other than hydrogen: ##STR127## where A is(CH₂)_(m) --Q--(CH₂)_(n), where m is 0 to 6 and n is 1 to 6 and Q is acovalent bond, O, S, SO, SO₂, NH, --SO₂ NH--, --NHSO₂ --, --CONH--,--NHCO--, --SO₂ N(C₁ -C₄ alkyl)--, --N(C₁ -C₄ alkyl)SO₂ --, --CON(C₁ -C₄alkyl)--, --N(C₁ -C₄ alkyl)CO--, --CH═CH--, --CO--, --OC(O)--, --C(O)O--or N(C₁ -C₄ alkyl) and (CH₂)_(m) is attached to the benzocoumarinylmoiety; ##STR128## is a 5- or 6-membered monocyclic heterocycle or an8-, 9- or 10-membered bicyclic heterocycle, the heterocycle containing afirst nitrogen in an aromatic 5- or 6-membered first ring, withattachment of the heterocycle to A by way of said first nitrogen andsaid first nitrogen is quaternary by virtue of the attachment and ringbonds, with the first ring containing 0 or 1 of either O or S, with thefirst ring containing 0 to 3 additional nitrogen atoms, with the firstring optionally fused to a 3- or 4-membered moiety to form the optionalsecond ring, with the the moiety containing at least one carbon atom,with the moiety containing 0 or 1 of either O or S, with the moietycontaining 0 to 2 nitrogen atoms, and with the moiety being saturated orunsaturated and the second ring aromatic or non-aromatic; R^(c) is R^(a)as defined under II below, hydrogen, or --NR^(y) R^(z) (where R^(y) andR^(z) are defined in II below), but independently selected from R^(a)and from each other if more than one R^(c) is present, and is attachedto a carbon ring atom or a nitrogen heteroatom the valency of which isnot satisfied by the ring bonds; p is 0 or 1; ##STR129## where##STR130## is a 5- or 6-membered monocyclic heterocycle or an 8-, 9- or10-membered bicyclic heterocycle, the heterocycle containing a firstnitrogen in an aromatic 5- or 6-membered first ring, with said firstnitrogen quaternary by virtue of a substituent R^(d) in addition to thering bonds thereto, with said first nitrogen neutral in the absence of asubstituent R^(d), with attachment of the heterocycle to A' by way of acarbon atom of a ring, with the first ring containing 0 or 1 of either Oor S, with the first ring containing 0 to 2 additional nitrogen atoms,with the first ring optionally fused to a 3- or 4-membered moiety toform the optional second ring, with the moiety containing at least onecarbon atom, with the moiety containing 0 or 1 of either O or S, withthe moiety containing 0 to 2 nitrogen atoms, and with the moiety beingsaturated or unsaturated and the second ring aromatic or non-aromatic;R^(c) is defined above; R^(d) is hydrogen, NH₂, O⁻ or C₁ -C₄ alkyl(where the alkyl group is optionally mono-substituted with R^(q) asdefined under IIc below); A' is (CH₂)_(m) --Q--(CH₂)_(n), where m is 0to 6 and n is 0 to 6 and Q is given above;c) --A_(p) --N⁺ R^(y)(R^(w)).sub.(0-1) (R^(z))where R^(y) and R^(z) are as defined under IIbelow, R^(y) and R^(z) may further be together a C₂ -C₄ alkylideneradical to form a ring (optionally mono-substituted with R^(q) asdefined below) interrupted by N(O)R^(e) or N⁺ (R^(e))₂ (where R^(e) ishydrogen, C₁ -C₄ alkyl, or C₁ -C₄ alkyl substituted with R^(q) definedbelow), R^(w) is hydrogen, C₁₋₄ alkyl, O⁻, NH₂ or absent in which casethe nitrogen is neutral, R^(w), R^(y) and R^(z) may further togetherform a C₅ -C₁₀ tertiary alkylidene radical which with N⁺ forms abicyclic ring, where the tertiary alkylidene radical is optionallymono-substituted with R^(q) as defined below and where the tertiarycarbon of the tertiary alkylidene radical is optionally replaced withnitrogen, N⁺ R^(e) (where R^(e) is defined above), or N⁺ -O⁻, p is 0 or1, and A is as defined above; ##STR131## where ##STR132## is a 5- or6-membered monocyclic heterocycle or an 8-, 9- or 10-membered bicyclicheterocycle, the heterocycle containing a first nitrogen in a firstring, with the first ring saturated or unsaturated and non-aromatic,with the first nitrogen quaternary by virtue of one or two substituentsR^(d) in addition to the ring bonds thereto, with the first nitrogenalternatively neutral by virtue of zero or one substituent R^(d) inaddition to the ring bonds thereto, with attachment of the heterocycleto A' by way of a carbon atom or non-quaternary nitrogen atom of a ring,with the first ring containing in addition to carbon and the firstnitrogen 0 to 1 of a member selected from the group consisting of thenon-quaternary nitrogen of attachment, O, S, S(O), S(O)₂ and NR^(e)where R^(e) is defined above, with the first ring optionally fused to a2-, 3- or 4-membered moiety to form the optional second ring, with themoiety optionally containing in addition to carbon the non-quaternarynitrogen of attachment, and with the moiety saturated or unsaturated andthe second ring non-aromatic; R^(d) is defined above and where more thanone R^(d) is present on a nitrogen, at least one R^(d) is hydrogen or C₁-C₄ alkyl; A' is defined above; and p is defined above; R^(q) is definedbelow;with the Type I, R^(a) substituent balanced with the anionic formof Z where Z is a methanesulfonyloxy, trifluoromethanesulfonyloxy,fluorosulfonyloxy, p-toluenesulfonyloxy,2,4,6-triisopropylbenzenesulfonyloxy, p-bromobenzenesulfonyloxy,p-nitrobenzenesulfonyloxy, bromo and iodo; II.a) a trifluoromethylgroup: --CF₃ ; b) a halogen atom: --Br, --Cl, --F, or --I; c) C₁ -C₄alkoxy radical: --OC₁₋₄ alkyl, wherein the alkyl is optionallymono-substituted by R^(q), where R^(q) is a member selected from thegroup consisting of --OH, --OP', --OCH₃, --CN, --C(O)NH₂, --OC(O)NH₂,CHO, --OC(O)N(CH₃)₂, --SO₂ NH₂, --SO₂ N(CH₃)₂, --SOCH₃, --SO₂ CH₃, --F,--CF₃, --COOM^(a) (where M^(a) is hydrogen, alkali metal, methyl, phenylor M defined below), tetrazolyl (where the point of attachment is thecarbon atom of the tetrazole ring and one of the nitrogen atoms ismono-substituted by M^(a) as defined above) and --SO₃ M^(b) (where M^(b)is hydrogen or an alkali metal or M defined below);d) a hydroxy orprotected hydroxy: --OH or --OP'; e) a carbonyloxy radical:--O(C═O)R^(s), where R^(s) is C₁₋₄ alkyl or phenyl, each of which isoptionally mono-substituted by R^(q) as defined above or tri-substitutedwith --F;f) a carbamoyloxy radical: --O(C═O)N(R^(y))R^(z) where R^(y)and R^(z) are independently H, C₁₋₄ alkyl (optionally mono-substitutedby R^(q) as defined above), together a 3- to 5-membered alkylideneradical to form a ring (optionally substituted with R^(q) as definedabove) or together a 2- to 4-membered alkylidene radical, interrupted by--O--, --S--, --S(O)-- or --S(O)₂ --, to form a ring (where the ring isoptionally mono-substituted with R_(q) as defined above);g) a sulfurradical: --S(O)_(n) --R^(s) where n=0-2, and R^(s) is defined above; h)a sulfamoyl group: --SO₂ N(R^(y))R^(z) where R^(y) and R^(z) are asdefined above; i) azido: N₃ j) a formamido group: --N(R^(t))(C═O)H,where R^(t) is H or C₁₋₄ alkyl, and the alkyl thereof is optionallymono-substituted by R^(q) as defined above;k) a (C₁ -C₄alkyl)carbonylamino radical: --N(R^(t))(C═O)C₁₋₄ alkyl, where R^(t) isas defined above, and the alkyl group is also optionallymono-substituted by R^(q) as defined above; l) a (C₁ -C₄ alkoxy)carbonylamino radical: --N(R^(t))(C═O)OC₁₋₄ alkyl, where R^(t) is asdefined above, and the alkyl group is also optionally mono-substitutedby R^(q) as defined above; m) a ureido group:--N(R^(t))(C═O)N(R^(y))R^(z) where R^(t), R^(y) and R^(z) are as definedabove; n) a sulfonamido group: --N(R^(t))SO₂ R^(s), where R^(s) andR^(t) are as defined above; o) a cyano group: --CN; p) a formyl oracetalized formyl radical: --(C═O)H or --CH(OCH₃)₂ ; q) (C₁ -C₄alkyl)carbonyl radical wherein the carbonyl is acetalized: --C(OCH₃)₂C₁₋₄ alkyl, where the alkyl is optionally mono-substituted by R^(q) asdefined above; r) carbonyl radical: --(C═O)R^(s), where R^(s) is asdefined above; s) a hydroximinomethyl radical in which the oxygen orcarbon atom is optionally substituted by a C₁ -C₄ alkyl group:--(C═NOR^(z))R^(y) where R^(y) and R^(z) are as defined above, exceptthey may not be joined together to form a ring; t) a (C₁ -C₄alkoxy)carbonyl radical: --(C═O)OC₁₋₄ alkyl, where the alkyl isoptionally mono-substituted by R^(q) as defined above; u) a carbamoylradical: --(C═O)N(R^(y))R^(z) where R^(y) and R^(z) are as definedabove; v) an N-hydroxycarbamoyl or N(C₁ -C₄ alkoxy)carbamoyl radical inwhich the nitrogen atom may be additionally substituted by a C₁ -C₄alkyl group: --(C═O)--N(OR^(y))R^(z) where R^(y) and R^(z) are asdefined above, except they may not be joined together to form a ring; w)a thiocarbamoyl group: --(C═S)N(R^(y))(R^(z)) where R^(y) and R^(z) areas defined above; x) carboxyl: --COOM^(b), where M^(b) is as definedabove; y) thiocyanate: --SCN; z) trifluoromethylthio: --SCF₃ ; aa)tetrazolyl, where the point of attachment is the carbon atom of thetetrazole ring and one of the nitrogen atoms is mono-substituted byhydrogen, an alkali metal or a C₁ -C₄ alkyl optionally substituted byR^(q) as defined above; ab) an anionic function selected from the groupconsisting of: phosphono [P═O(OM^(b))₂ ]; alkylphosphono{P═O(OM^(b))--[O(C₁ -C₄ alkyl)]}; alkylphosphinyl [P═O(OM^(b))--(C₁ -C₄alkyl)]; phosphoramido [P═O(OM^(b))N(R^(y))R^(z) and P═O(OM^(b))NHR^(x)]; sulfino (SO₂ M^(b)); sulfo (SO₃ M^(b)); acylsulfonamides selectedfrom the structures CONM^(b) SO₂ R^(x), CONM^(b) SO₂ N(R^(y))R^(z), SO₂NM^(b) CON(R^(y))R^(z) ; and SO₂ NM^(b) CN, where R^(x) is phenyl orheteroaryl, where heteroaryl is a monocyclic aromatic hydrocarbon grouphaving 5 or 6 ring atoms, in which a carbon atom is the point ofattachment, in which one of the carbon atoms has been replaced by anitrogen atom, in which one additional carbon atom is optionallyreplaced by a heteroatom selected from O or S, and in which from 1 to 2additional carbon atoms are optionally replaced by a nitrogenheteroatom, and where the phenyl and heteroaryl are optionallymono-substituted by R^(q), as defined above; M^(b) is as defined above;and R^(y) and R^(z) are as defined above;ac) C₅ -C₇ cycloalkyl group inwhich one of the carbon atoms in the ring is replaced by a heteroatomselected from O, S, NH or N(C₁ -C₄ alkyl) and in which one additionalcarbon atom may be replaced by NH or N(C₁ -C₄ alkyl), and in which atleast one carbon atom adjacent to each nitrogen heteroatom has both ofits attached hydrogen atoms replaced by one oxygen thus forming acarbonyl moiety and there are one or two carbonyl moieties present inthe ring; ad) C₂ -C₄ alkenyl radical, optionally mono-substituted by oneof the substitutents a) to ac) above the phenyl which is optionallysubstituted by R^(q) as defined above; ae) C₂ -C₄ alkynyl radical,optionally mono-substituted by one of the substituents a) to ac) above;af) C₁ -C₄ alkyl radical; ag) C₁ -C₄ alkyl mono-substituted by one ofthe substituents a)-ac) above; ah) a 2-oxazolidinonyl moiety in whichthe point of attachment is the nitrogen atom of the oxazolidinone ring,the ring oxygen atom is optionally replaced by a heteroatom selectedfrom --S-- and NR^(t) (where R^(t) is as defined above) and one of thesaturated carbon atoms of the oxazolidinone ring is optionallymono-substituted by one of the substituents a) to ag) above; and M is aremovable protecting group for carboxy.
 2. The compound of claim 1wherein M is selected from the group consisting of alkyl, substitutedalkyl, benzyl, substituted benzyl, aryl, substituted aryl, allyl,substituted allyl and triorganosilyl.
 3. The compound of claim 1 whereinM is selected from the group consisting of benzhydryl, p-nitrobenzyl,2-naphthylmethyl, allyl, 2-chloroallyl, benzyl, t-butyl,2,2,2-trichloroethyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,trimethylsilyl, 2-(trimethyl)silylethyl, phenacyl, p-methoxybenzyl,acetonyl, o-nitrobenzyl and 4-pyridylmethyl.
 4. The compound of claim 1wherein P' is selected from the group consisting of trialkylsilyl,aryl(alkyl)alkoxysilyl, alkoxydiarylsilyl and diarylalkylsilyl andcarbonate groups such as alkyloxycarbonyl, substituted alkyloxycarbonyl,benzyloxycarbonyl, substituted benzyloxycarbonyl, allyloxycarbonyl andsubstituted allyloxycarbonyl.
 5. The compound of claim 1 wherein P' isselected from the group consisting of t-butylmethoxyphenylsilyl,t-butoxydiphenylsilyl, trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, o-nitrobenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, t-butyloxycarbonyl,2,2,2-trichloroethyloxycarbonyl and allyloxycarbonyl.
 6. A compound ofthe formula: ##STR133## wherein R is --H or --CH₃ ;R^(a) is selectedfrom the group consisting of H, OP', Cl, Br, I, SCH₃, CN, CHO, SOCH₃,SO₂ CH₃, CO₂ M, CH₂ OP' or CONH₂ ; P' is a removable protecting groupfor hydroxy; M is a removable protecting group for carboxy; and Z isselected from the group consisting of alkylsulfonyloxy, substitutedalkylsulfonyloxy, arylsulfonyloxy, substituted arylsulfonyloxy,fluorosulfonyloxy, and halogen; andwith the proviso that the --CH₂ --Zmoiety is in the 3- or 4-position of the benzocoumarin as numberedabove.
 7. The compound of claim 6 wherein M is selected from the groupconsisting of alkyl, substituted alkyl, benzyl, substituted benzyl,aryl, substituted aryl, allyl, substituted allyl and triorganosilyl. 8.The compound of claim 6 wherein M is selected from the group consistingof benzhydryl, p-nitrobenzyl, 2-naphthylmethyl, allyl, 2-chloroallyl,benzyl, t-butyl, 2,2,2-trichloroethyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, trimethylsilyl, 2-(trimethyl)silylethyl, phenacyl,p-methoxybenzyl, acetonyl, o-nitrobenzyl and 4-pyridylmethyl.
 9. Thecompound of claim 6 wherein P' is selected from the group consisting oftrialkylsilyl, aryl(alkyl)alkoxysilyl, alkoxydiarylsilyl anddiarylalkylsilyl and carbonate groups such as alkyloxycarbonyl,substituted alkyloxycarbonyl, benzyloxycarbonyl, substitutedbenzyloxycarbonyl, allyloxycarbonyl and substituted allyloxycarbonyl.10. The compound of claim 6 wherein P' is selected from the groupconsisting of t-butylmethoxyphenylsilyl, t-butoxydiphenylsilyl,trimethylsilyl, triethylsilyl, t-butyldimethylsilyl,o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl,t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl andallyloxycarbonyl.
 11. The compound of claim 6 wherein Z is selected fromthe group consisting of methanesulfonyloxy, trifluoromethanesulfonyloxy,fluorosulfonyloxy, p-toluenesulfonyloxy,2,4,6-isopropylbenzenesulfonyloxy, p-bromobenzenesulfonyloxy,p-nitrobenzenesulfonyloxy, bromo and iodo.